Synthesis of desosamines

ABSTRACT

The present invention provides desosamine and mycaminose analogs and nitro sugars and methods for their preparation. The invention also provides methods of cyclizing a compound of Formula (A′) with glyoxal to give a nitro sugar of Formula (B). Methods for the preparation of compound of Formula (D′) are provided comprising cyclization of a nitro alcohol to give a nitro sugar and reduction and alkylation of the nitro sugar to give a desosamine, mycaminose, or an analog thereof.

RELATED APPLICATIONS

The present application is a continuation of and claims priority under35 U.S.C. § 120 to U.S. patent application U.S. Ser. No. 15/558,910,filed Sep. 15, 2017, which is a national stage filing under 35 U.S.C. §371 of international application, PCT/US2016/024210, filed Mar. 25,2016, which claims priority under 35 U.S.C. § 119(e) to U.S. provisionalpatent application, U.S. Ser. No. 62/138,168, filed Mar. 25, 2015, eachof which is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under AI058395 awardedby the National Institutes of Health. The government has certain rightsin the invention.

BACKGROUND

Emerging resistance to existing antibiotics is rapidly developing as acrisis of global proportions, especially for Staphylococcus aureus,Streptococcus pyogenes, and Streptococcus pneumonia infections.Pathogenic bacteria can transmit genes coding for antibiotic resistanceboth vertically (to their progeny) and horizontally (to neighboringbacteria of different lineages), and as a result antibiotic resistancecan evolve quickly, particularly in nosocomial (hospital) settings. See,e.g., Wright, Chem. Commun. (2011) 47:4055-4061. This year, >99,000people will die in the U.S. from healthcare-associated infections, morethan all casualties from car accidents, HIV, and breast cancer combined,creating an estimated burden of up to $45 billion in U.S. healthcarecosts. See, e.g., Klevens et al., Public Health Rep. (2007) 122:160-166.The current crisis is exacerbated by the fact that most majorpharmaceutical companies have essentially abandoned research in thedevelopment of new antibiotics. See, e.g., Projan, Curr. Opin.Microbiol. (2003) 6:427-430. The current rate of introduction of newantibiotics does not adequately address growing resistance, and with theease of international travel and increasing population densities, theneed for innovation in the field has never been higher.

The sugars desosamine and mycaminose are critical components of manymacrolide antibiotics. For the development of practical and scalablesynthetic routes to macrolide antibiotics and novel analogs, there is aneed for simple and efficient methods of preparing desosamine,mycaminose, and analogs thereof.

SUMMARY OF THE INVENTION

The present invention describes methods of preparing desosamine andmycaminose, and analogs thereof; intermediates in their preparation; andnovel desosamine and mycaminose analogs. D-desosamine and D-mycaminoseare monosaccharides with the following structures:

D-desosamine is a component of erythromycin, and many other macrolideantibiotics (e.g., tylosin, azithromycin, solithromycin, cethromycin)feature a desosamine or mycaminose sugar attached to the macrolide atthe C5 position. X-ray crystallographic studies reveal that both sugarsmake extensive contacts with the 23S subunit of bacterial ribosomal RNA,and thus it is thought that they play key roles in antibiotic activity.See, e.g., Tu et al., Cell (2005) 121:257-270; Mankin et al., CurrentOpinion in Microbiology (2008) 11:414-421. Variation of the C5 sugarwith desosamine or mycaminose derivatives may afford macrolideantibiotics with desired pharmaceutical properties (e.g., efficacyversus resistant strains, improved pharmacokinetics, reducedside-effects).

Since the structure of desosamine was determined in 1962, a number ofsyntheses of the compound have been reported. See, e.g., Korte et al.,Tetrahedron Lett. (1962) 18:657-666; Newman, J. Org. Chem. (1964)29:1461-1468; Richardson, J. Chem. Soc. (1964) 5364-5370; Baer et al.,Can. J. Chem. (1974) 52:122-124; Davidson et al., Org. Lett. (2004)6:1601-1603; Velvadapu et al., Carbohydr. Res. (2008) 343:145-150.Richardson, Davidson et al., and Velvadapu et al., in particular, havereported stereospecific approaches to the naturally occurringenantiomer, D-desosamine. Richardson's synthesis from3-acetoamido-4,6-O-benzylidiene-3-deoxy-D-α-glucopyranoside proceeded in8 steps and 1.6% yield. Davidson et al. reported an 11-step synthesis ofD-desosamine-1,2-diacetate that featured a tungsten-catalyzed alkynolcycloisomerization. This route employed(R)-3-tert-butyldimethylsiloxybutanal as starting material and proceededin 13% overall yield. Velvadapu et al. published a 5-step route toD-desosamine employing methyl D-α-glucopyranoside as the startingmaterial and proceeded in 16% overall yield. Desosamine can also beobtained from erythromycin by acidic hydrolysis, but the process islaborious and low-yielding.

We provide a practical and efficient method of preparing a desosamine,mycaminose, or analog thereof. Starting with a nitro alcohol of Formula(A):

the synthesis of a desosamine or mycaminose analog can be accomplishedin a few steps. First, the nitro alcohol of Formula (A) is cyclized withglyoxal:

to yield a nitro sugar of Formula (B):

Following optional protection to yield a nitro sugar of Formula (B′):

the nitro sugar is reduced to transform the nitro group into an amine.The resulting amino sugar of Formula (C′):

is then alkylated or protected to give a desosamine or mycaminose ofFormula (D′):

Definitions for the substituents R¹, R², R³, R^(4a), R^(4b), R⁵, R⁶, R⁷,and R⁸ are provided in the Detailed Description.

The nitro alcohol of Formula (A) may be prepared by any method. Anexample is the following two step procedure from a vinyl ketone.Addition of a nitro group to the vinyl ketone of Formula (Q):

affords a nitro ketone of Formula (R):

which is then reduced to yield the nitro alcohol of Formula (A).

The desosamine and mycaminose analogs may be modified to prepareglycosyl donors (e.g., to be used in the glycosylation step of amacrolide synthesis). A method provided herein for preparing athioglycoside desosamine or mycaminose derivative comprises the steps ofoptionally protecting a compound of Formula (D′) to yield a compound ofFormula (E′):

and contacting a compound of Formula (E′) with 2-mercaptopyrimidine toform a thioglycoside of Formula (F′):

wherein R¹, R², R³, R^(4a), R^(4b), P^(O1), P^(O2), R^(TG), R⁷, and R⁸are as defined herein.

The present disclosure provides novel desosamine and mycaminose analogs,as a compound of Formula (J):

or salt thereof. In addition, the intermediate nitro sugar is providedas a compound of Formula (K):

or a salt thereof. See the Detailed Description for definitions ofR^(1b), R^(2b), R^(3b), R^(4a), R^(4b), R⁵, R⁶, R⁷ and R⁸.

The details of certain embodiments of the invention are set forth in theDetailed Description of Certain Embodiments, as described below. Otherfeatures, objects, and advantages of the invention will be apparent fromthe Definitions, Examples, Figures, and Claims.

BRIEF DESCRIPTION OF THE DRAWING

The accompanying drawing, which constitute a part of this specification,illustrate several embodiments of the invention and together with thedescription, serve to explain the principles of the invention.

FIG. 1. Synthetic scheme of desosamine and mycaminose analogs, andsynthesis of D-desosamine.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

Desosamine (3-(dimethylamino)-3,4,6-trideoxyhexose) is a monosaccharidewith a structure of the formula:

The carbons are numbered from 1 to 6 following the convention for hexosesugars and are referred to herein as C1, C2, C3, C4, C5, and C6. Thereare several possible stereoisomers of desosamine, and analogs thereof.The stereoisomer found in many macrolides containing desosamine isD-desosamine of the structure:

Those skilled in the art will recognize that the stereochemistry at thehemiacetal carbon (C1) of D-desosamine may be of either the (R) or (S)configuration, and those configurations may interconvert through theprocess of anomerization. Typically the two anomers are in equilibriumwhen the sugar is in solution. The cyclic hemiacetal forms are also inequilibrium with a linear form, which is an intermediate of theanomerization process, and for D-desosamine is of formula:

As used herein, the term “desosamine,” when not only referring to3-(dimethylamino)-3,4,6-trideoxyhexose, encompasses desosamine,desosamine analogs, desosamine derivatives, and protected desosamines.Mycaminose is a monosaccharide of similar structure to desosamine with ahydroxyl group at the C4 position, as in the following structures:

The term “mycaminose,” when not only referring to3-(dimethylamino)-3,6-dideoxyhexose, encompasses mycaminose, mycaminoseanalogs, mycaminose derivatives, and protected mycaminoses. The C4position of a desosamine is substituted with two hydrogen atoms, whilethe C4 position of a mycaminose has at least one non-hydrogensubstituent (e.g., hydroxyl, alkoxy).

In the case of desosamine itself methods herein provide a four-steproute to the sugar. The process described herein provides a synthesis ofhighly enantiomerically enriched D-desosamine from methyl vinyl ketone(See FIG. 1). The method is suitable for large-scale synthesis andrequires no chromatography. In other aspects, the method provides asynthetic route to analogs of desosamine and enantiomerically enricheddesosamine derivatives. The invention also contemplates analogs of bothdesosamine and mycaminose and related sugars. The synthesis ofdesosamine, mycaminose, and analogs thereof may, in some embodiments, beaccomplished in four steps (e.g., from a vinyl ketone), or depending onthe compound, intermediates, and starting materials necessary mayrequire fewer or more steps. Desosamines include compounds withsubstitution at any or all positions of desosamine. The methods hereinmay afford desosamines as either neutral compounds or salts.

The invention is, in part, directed to methods of synthesizingdesosamine and mycaminose analogs. As generally described herein, thedesosamine or mycaminose is prepared according to Scheme 1. First, acompound of Formula (A) is cyclized with glyoxal (C₂H₂O₂) to yield acompound of Formula (B). Second, the compound of Formula (B), a nitrosugar, is reduced to yield a compound of Formula (C′), an amino sugar.Third, the compound of Formula (C′) is alkylated or protected to yield acompound of Formula (D′). The second and third steps may be performed ina single procedure, i.e., without isolation of the amino sugar. Thesynthesis may be carried out without protection of the C1 and C2 hydroxypositions, in which case R⁵ and R⁶ are hydrogen for compounds of bothFormula (C′) and (D′). Alternatively, the hydroxy positions may beprotected prior to the step of reducing to transform a compound ofFormula (B) into a compound of Formula (B′). The compound of Formula(B′) would then be reduced to yield a compound of Formula (C′) andsubsequently alkylated or protected to yield a compound of Formula (D′).

The compound of Formula (A) may be prepared according to Scheme 2. Anitro group is added to a vinyl ketone of Formula (Q), to yield aβ-nitro ketone of Formula (R). The compound of Formula (R) is thenreduced to yield the compound of Formula (A).

The schemes provided are not limiting, and the disclosure contemplatesmethods wherein additional steps are added, existing steps are omittedor substituted, or the order of steps is altered. For example, forcertain functional groups, additional protection or deprotection stepsmay be necessary or desired to maintain compatibility with certainreactions or reagents. The synthetic steps, formulae of startingmaterial, intermediates, and products, and substituents therein arefurther defined below.

Methods of Preparing a Desosamine, Mycaminose, or Analog Thereof

In certain embodiments, the invention provides methods for thepreparation of a compound of Formula (D′):

or salt thereof, wherein:

-   -   R¹ is hydrogen, halogen, optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted carbocyclyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, —OR^(S), —N(R^(S))₂, —NR^(S)(OR^(S)),        —SR^(S), —SSR^(S), —Si(R^(S))₃, —OSi(R^(S))₃, or of formula:

-   -   each of R² and R³ is independently hydrogen, halogen, optionally        substituted C₁-C₆ alkyl, —OR^(SO), or —N(R^(SN))₂.    -   L^(S1) is a bond, —NR^(S)—, —O—, or —S—, or a linking group        selected from the group consisting of optionally substituted        alkylene, optionally substituted alkenylene, optionally        substituted alkynylene, optionally substituted heteroalkylene,        optionally substituted heteroalkenylene, and optionally        substituted heteroalkynylene, and combinations thereof;    -   X^(S) is a bond, —C(═O)—, —C(═NR^(SN))—, —S(═O)—, or —S(═O)₂—;    -   L^(S2) is a bond, —NR^(S)—, —O—, or —S—, or a linking group        selected from the group consisting of optionally substituted        alkylene, optionally substituted alkenylene, optionally        substituted alkynylene, optionally substituted heteroalkylene,        optionally substituted heteroalkenylene, and optionally        substituted heteroalkynylene, and combinations thereof;    -   each R^(S) is independently hydrogen, optionally substituted        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted carbocyclyl, optionally        substituted heterocyclyl, optionally substituted aryl,        optionally substituted heteroaryl, an oxygen protecting group        when attached to an oxygen atom, a nitrogen protecting group        when attached to a nitrogen atom, or a sulfur protecting group        when attached to a sulfur atom, or two R^(S) attached to the        same nitrogen atom are taken together to form ═N₂ or an        optionally substituted heterocyclyl or heteroaryl ring;    -   each of R⁷ and R⁸ is independently hydrogen, optionally        substituted C₁-C₆ alkyl, optionally substituted carbocyclyl,        optionally substituted aryl, optionally substituted        heterocyclyl, optionally substituted heteroaryl, optionally        substituted acyl, or a nitrogen protecting group, or R⁷ and R⁸        are joined to form an optionally substituted heterocyclyl or        heteroaryl ring;    -   each R^(SN) is independently hydrogen, optionally substituted        C₁-C₆ alkyl, or a nitrogen protecting group, or two R^(SN)        attached to the same nitrogen atom are joined to form an        optionally substituted heterocyclyl or heteroaryl ring;    -   each of R^(4a) and R^(4b) is independently hydrogen, halogen,        optionally substituted C₁-C₆ alkyl, or —OR^(SO); and    -   each of R⁵, R⁶ and R^(SO) is independently hydrogen, optionally        substituted C₁-C₆ alkyl, a carbohydrate, or an oxygen protecting        group.

Unless otherwise stated, any formulae described herein are also meant toinclude salts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, and isotopically labeled derivatives thereof. In certainembodiments, the provided compound is a salt of any of the formulaedescribed herein. In certain embodiments, the provided compound is apharmaceutically acceptable salt of any of the formulae describedherein. In certain embodiments, the provided compound is a solvate ofany of the formulae described herein. In certain embodiments, theprovided compound is a hydrate of any of the formulae described herein.In certain embodiments, the provided compound is a polymorph of any ofthe formulae described herein. In certain embodiments, the providedcompound is a co-crystal of any of the formulae described herein. Incertain embodiments, the provided compound is a tautomer of any of theformulae described herein. In certain embodiments, the provided compoundis a stereoisomer of any of the formulae described herein. In certainembodiments, the provided compound is of an isotopically labeled form ofany of the formulae described herein. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, replacement of ¹⁹F with ¹⁸F, or the replacement of a ¹²C bya ¹³C or ¹⁴C are within the scope of the disclosure. In certainembodiments, the provided compound is a deuterated form of any of theformulae described herein.

A compound of Formula (D′) may be provided by alkylating or protectingthe amine at the C3 position. In certain embodiments, the inventionprovides methods of preparing a compound of Formula (D′):

or salt thereof, comprises alkylating or protecting a compound ofFormula (C′):

or salt thereof, with an alkylating or protecting agent, wherein R¹, R²,R³, R^(4a), R^(4b), R⁵, R⁶, R⁷, and R⁸ are as defined herein.

In certain embodiments, for the step of alkylating or protecting acompound of Formula (C′), the compound of Formula (C′) is a salt ofFormula (C—X′):

and the step of alkylating or protecting is performed in the presence ofa base, and X_(c) ⁻ is an anion. In certain embodiments, X_(c) ⁻ isselected the group consisting of halide, H₃CC(═O)O⁻, NO₃ ⁻, ClO₄ ⁻, OH⁻,H₂PO₄ ⁻, HCO₃ ⁻ HSO₄ ⁻, sulfonates, carboxylates, carboranes, BF₄ ⁻, PF₄⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆ ⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, BPh₄ ⁻, andAl(OC(CF₃)₃)₄ ⁻. In some embodiments, X_(c) ⁻ is fluoride. In someembodiments, X_(c) ⁻ is chloride, bromide, or iodide. In someembodiments, X_(c) ⁻ is acetate.

The alkylation step may comprise dimethylation of the amine to give adimethylamino group. When this demethylation is carried out with aqueousformaldehyde, the reaction is known as the Eschweiler-Clarke reaction.In some embodiments, the alkylating agent is formaldehyde. In someembodiments, the step of alkylating with formaldehyde is performed inthe presence of formic acid. In some embodiments, the step of alkylatingwith formaldehyde is performed in the presence of sodiumcyanoborohydride. In some embodiments, the alkylating agent is benzylbromide. In some embodiments, the protecting agent is di-tert-butyldicarbonate (Boc₂O). In some embodiments, the step of alkylating orprotecting is performed in the presence of a base (e.g., a carbonate, abicarbonate). In some embodiments, the alkylating agent is anorganomagnesium, organolithium, organocopper, organozinc, organosodium,or organopotassium reagent. In some embodiments, the alkylating reagentis an alkyl halide. In some embodiments, the alkylating agent isbromomethane, diazoamethane, 2,2-dimethoxypropane, dimethyl carbonate,dimethyl dicarbonate, dimethyl sulfate, 1,2-dimethylhydrazine,dimethylzinc, methyl fluorosulfonate, methyl iodide, methylmethansulfonate, methyl trifluoromethanesulfonate, methylcobalamin, ortrimetyloxonium tetrafluoroborate. In some embodiments, the step ofalkylating or protecting is performed in the presence of a protectingagent and a base (e.g., a carbonate, a bicarbonate).

The protecting agent may be any reagent suitable for modifying an aminewith a nitrogen protecting group, as defined herein. In someembodiments, the protecting agent is benzyl chloroformate,fluorenylmethyloxycarbonyl chloride, acetic anhydride, acetyl chloride,benzoyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonylchloride, 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonylchloride, methanesulfonyl chloride, or trifluoromethanesulfonylchloride. In some embodiments, the step of protecting is performed inthe presence of a protecting agent and a base (e.g., a carbonate, abicarbonate).

A compound of Formula (C′) may be provided by reducing the nitro groupof a compound of Formula (B′) to yield an amino group. In certainembodiments, the method of preparing a compound of Formula (C′):

or salt thereof, comprises reducing a compound of Formula (B′):

or salt thereof, wherein R¹, R², R³, R^(4a), R^(4b), R⁵, and R⁶ are asdefined herein. In certain embodiments, R⁵ and R⁶ are hydrogen. Incertain other embodiments, the method further comprises protecting acompound of Formula (B):

or salt thereof, to yield a compound of Formula (B′), or salt thereof.In some embodiments, the step of reducing is performed in the presenceof H₂ and a catalyst. In some embodiments, the catalyst comprisespalladium hydroxide. In some embodiments, the catalyst comprisespalladium, platinum, rhodium, ruthenium, iridium, cobalt, iron, ornickel. In some embodiments, the catalyst is palladium on carbon orRaney nickel. In some embodiments, the step of reducing is performed inthe presence of formic acid, a borane, an ammonium salt, or a silane.

A compound of Formula (B) may be provided by cyclizing a compound ofFormula (A) with glyoxal. Glyoxal may be represented by the followingstructure:

but may also exist in various hydrated and/or oligomeric forms. Incertain embodiments, the method of preparing a compound of Formula (B):

or salt thereof, comprises cyclizing an alcohol of Formula (A):

or salt thereof, with glyoxal:

wherein R¹, R², R³, R^(4a), and R^(4b) are as defined herein. In certainembodiments, the step of cyclizing is performed in the presence of abase. In certain embodiments, the step of cyclizing is performed in thepresence of aqueous glyoxal. In certain embodiments, the step ofcyclizing is performed in water. In certain embodiments, the step ofcyclizing is performed in a biphasic mixture (e.g., water and animmiscible organic solvent). In some embodiments, the biphasic mixturecomprises dichloromethane and water. In certain embodiments, the step ofcyclizing is performed in water or a biphasic mixture in the presence ofa base. In some embodiments, the base is a carbonate.

The step of cyclizing may be stereoselective, for instance when aparticular stereoisomer of a compound of Formula (A) is provided. Incertain embodiments, the compound of Formula (B), or salt thereof, is ofFormula (B-1):

or salt thereof; and the alcohol of Formula (A) is of Formula (A-1):

or salt thereof. In certain embodiments, the compound of Formula (B), orsalt thereof, is of Formula (B-2):

or salt thereof; and the alcohol of Formula (A) is of Formula (A-2):

or salt thereof. In certain embodiments, the compound of Formula (B) isobtained in at least about 50% enantiomeric excess, at least about 75%enantiomeric excess, at least about 90% enantiomeric excess, at leastabout 95% enantiomeric excess, at least about 97% enantiomeric excess,or at least about 99% enantiomeric excess. In certain embodiments, thecompound of Formula (A) is provided in at least about 50% enantiomericexcess, at least about 75% enantiomeric excess, at least about 90%enantiomeric excess, at least about 95% enantiomeric excess, at leastabout 97% enantiomeric excess, or at least about 99% enantiomericexcess.

A compound of Formula (A) may be provided by reducing a β-nitro ketoneof Formula (R). In certain embodiments, the method of preparing acompound of Formula (A) comprises reducing a compound of Formula (R):

or salt thereof, to yield a compound of Formula (A), or salt thereof. Incertain embodiments, the step of reduction is stereoselective. In someembodiments, the compound of Formula (A) is a compound of Formula (A-1):

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-2):

In some embodiments, the compound of Formula (A) is obtained in at leastabout 50% enantiomeric excess, at least about 75% enantiomeric excess,at least about 90% enantiomeric excess, at least about 95% enantiomericexcess, at least about 97% enantiomeric excess, or at least about 99%enantiomeric excess. In certain embodiments, the step of reducing isperformed in the presence of a borane and a chiral catalyst. In someembodiments, the borane is BH₃ or BH₃-THF complex. In some embodiments,the chiral catalyst is an oxazaborilidine. In some embodiments, thecatalyst is a Corey-Bakshi-Shibata catalyst. See, e.g., Corey et al., J.Am. Chem. Soc. (1987) 109:5551-5553; Angew. Chem. Int. Ed. (1998)37:1986-2012. In some embodiments, the catalyst is of formula:

wherein R^(CBS) is hydrogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy.

A compound of Formula (R) may be provided by adding a nitro group to avinyl ketone of Formula (Q). In certain embodiments, the method ofpreparing a compound of Formula (R) comprises adding a nitro group to acompound of Formula (Q):

or salt thereof, to yield a compound of Formula (R), or salt thereof. Incertain embodiments, the step of adding a nitro group comprisescontacting the compound of Formula (Q) with sodium nitrite. In certainembodiments, the step of adding a nitro group is performed in thepresence an acid. In certain embodiments, the step of adding a nitrogroup is performed in the presence of an acid and pyridine. In someembodiments, the acid is acetic acid or trifluoroacetic acid. In someembodiments, the acid is pyridinium trifluoroacetic acid.

In an another aspect, the invention provides methods for preparing aglycosyl donor derivative of a desosamine, mycaminose, or analogthereof. A glycosyl donor is a carbohydrate that will react to form aglycosidic bond with a suitable acceptor. For example, the hydroxylgroup of a macrolide (or macrolide precursor) may react with a glycosyldonor resulting in a glycosidic attachment of the desosamine ormycaminose to the macrolide (or precursor). Typical glycosyl donors havea leaving group attached to the anomeric carbon. Exemplary groups forthe anomeric leaving group include halogens, thioethers, acetimidates,acetate, phosphates, and O-pentenyl. A thioglycoside is sugar with athioether group at the anomeric carbon (C1). A method for preparingdesosamine or mycaminose thioglycosides is described in Scheme 3. First,a compound of Formula (D′) is optionally protected (e.g., when at leastone of R⁵ and R⁶ is hydrogen) to give a compound of Formula (E′). Theprotected desosamine is then treated with a reagent suitable to replacethe substituent at the anomer carbon with a leaving group, thus yieldinga compound of Formula (F′).

In certain embodiments, the method of preparing a compound of Formula(F′) comprises the steps of optionally protecting a compound of Formula(D′), or salt thereof, to yield a compound of Formula (E′):

or salt thereof, and substituting the anomer carbon of a compound ofFormula (E′), or salt thereof, with a leaving group to form a compoundof Formula (F′):

or salt thereof, wherein:

-   -   R¹, R², R³, R^(4a), R^(4b), R⁵, R⁶, R⁷, and R⁸ are as defined        herein;    -   each of P^(O1) and P^(O2) is independently optionally        substituted C₁-C₆ alkyl, or an oxygen protecting group; and    -   LG is a leaving group.

Exemplary methods of adding substituting the anomeric carbon with aleaving group are shown in Scheme 4. R^(TG) is optionally substitutedC₁-C₆ alkyl, optionally substituted phenyl, or optionally substitutedheteroaryl. X is a halogen or triflate. [X] is a halogen or triflatedonor (e.g., TMSCl, TMSBr, TMSI, TMSOTf, Bu₄NBr, Bu₄NI).

In certain embodiments, the leaving group is a halogen. In someembodiments, the leaving group is —F. In some embodiments, the leavinggroup is —Cl, —Br, or —I. In certain embodiments, the leaving group isan acetimidate (e.g., acetimidate, N-methylacetimidate,N-phenylacetimidate, trichloroacetimidate, N-methyltrichloroacetimidate,N-phenyltrichloroacetimidate, trifluoroacetimidate,N-methyltrifluoroacetimidate, N-phenyltrifluoroacetimidate). In certainembodiments, the leaving group is acetate. In certain embodiments, theleaving group is a phosphate. In certain embodiments, the leaving groupis —O(CH₂)₃CH═CH₂.

In certain embodiments, the leaving group is —SR^(TG). In someembodiments, R^(TG) is optionally substituted C₁-C₆ alkyl. In someembodiments, R^(TG) is C₁-C₆ alkyl. In some embodiments, R^(TG) isoptionally substituted aryl. In some embodiments, R^(TG) is phenyl. Insome embodiments, R^(TG) is heteroaryl. In some embodiments, R^(TG) ispyridinyl or pyramindyl. In some embodiments, —SR^(TG) is:

In certain embodiments, the step of substituting the anomeric carbonwith —SR^(TG) is performed in the presence of a boron trihalide (e.g.,BF₃). In certain embodiments, the step of substituting the anomericcarbon with —SR^(TG) is performed in the presence of a phosphine (e.g.,triphenyl phosphine) and an azodicarboxylate (e.g., diethylazodicarboxylate). In certain embodiments, the step of substituting theanomeric carbon with —SR^(TG) is performed in the presence of a silylcompound and a base. In some embodiments, the silyl compound is a silylhalide (e.g., trimethylsilyl chloride) or a silyl triflate (e.g.,trimethylsilyl triflate). In some embodiments, the base is a pyridine(e.g., pyridine, 2,4-lutidine, 2,6-lutidine). In some embodiments, thesilyl compound is trimethylsilyl triflate, and the base is 2,6-lutidine.

In certain embodiments, the step of protecting is performed in thepresence of methylchloroformate and a base (e.g., a carbonate, anamine). In some embodiments, the base is trimethylamine, trimethylamine,or diisopropylethylamine. The protecting groups P^(O1) and P^(O2) mayeach independently be any oxygen protecting group, as defined herein. Insome embodiments, P^(O1) is alkoxycarbonyl. In some embodiments, P^(O2)is alkoxycarbonyl. In some embodiments, P^(O1) and P^(O2) arealkoxycarbonyl. In some embodiments, P^(O1) is methoxycarbonyl. In someembodiments, P^(O2) is methoxycarbonyl. In some embodiments, P^(O1) andP^(O2) are methoxycarbonyl. In some embodiments, each of P^(O1) andP^(O2) are independently acetyl, benzoyl, benzyl, methoxymethyl ether,p-methoxybenzyl ether, methylthiomethylether, pivaloyl,tetrahydropyranyl, tetrahydrofuranyl, triphenylmethyl, or silyl (e.g.,trimethyl silyl, tert-butyldimethylsilyl, triisopropylsilyloxymethyl,triisopropylsilyl).

In certain embodiments, the method for preparing a compound of Formula(D′) is for the preparation of a compound listed in Table 1. The methodcontemplates both the α and β anomer, though only one anomer is drawnfor each compound in the table.

TABLE 1

Compounds of Formula (J)

In another aspect, the invention provides novel desosamine or mycaminoseanalogs which have not been previously disclosed. In certainembodiments, the desosamine or mycaminose analog is a compound ofFormula (J):

or salt thereof, wherein:

-   -   R^(1a) is —N(R^(S))₂, —NR^(S)(OR^(S)), or of formula:

-   -   each of R^(2a) and R^(3a) is independently hydrogen, halogen,        optionally substituted C₁-C₆ alkyl, or —OR^(SO).    -   X^(S) is a bond, —C(═O)—, —C(═NR^(SN))—, —S(═O)—, or —S(═O)₂—;    -   L^(S2) is a bond, —NR^(S)—, —O—, or —S—, or a linking group        selected from the group consisting of optionally substituted        alkylene, optionally substituted alkenylene, optionally        substituted alkynylene, optionally substituted heteroalkylene,        optionally substituted heteroalkenylene, and optionally        substituted heteroalkynylene, and combinations thereof;    -   each R^(S) is independently hydrogen, optionally substituted        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted carbocyclyl, optionally        substituted heterocyclyl, optionally substituted aryl,        optionally substituted heteroaryl, an oxygen protecting group        when attached to an oxygen atom, a nitrogen protecting group        when attached to a nitrogen atom, or a sulfur protecting group        when attached to a sulfur atom, or two R^(S) attached to the        same nitrogen atom are taken together to form ═N₂ or an        optionally substituted heterocyclyl or heteroaryl ring;    -   each of R^(7a) and R^(8a) is independently optionally        substituted C₁-C₆ alkyl, optionally substituted carbocyclyl,        optionally substituted aryl, optionally substituted        heterocyclyl, optionally substituted heteroaryl, optionally        substituted acyl, or a nitrogen protecting group, or R^(7a) and        R^(8a) are joined to form an optionally substituted heterocyclyl        or heteroaryl ring;    -   each R^(SN) is independently hydrogen, optionally substituted        C₁-C₆ alkyl, or a nitrogen protecting group, or two R^(SN)        attached to the same nitrogen atom are joined to form an        optionally substituted heterocyclyl or heteroaryl ring;    -   each of R^(4a) and R^(4b) is independently hydrogen, halogen,        optionally substituted C₁-C₆ alkyl, or —OR^(SO); and    -   each of R⁵, R⁶ and R^(SO) is independently hydrogen, optionally        substituted C₁-C₆ alkyl, a carbohydrate, or an oxygen protecting        group.

In certain embodiments, R^(1a) is not:

In certain embodiments, a compound of Formula (J) is a compound listedin Table 2. The invention contemplates both the α and β anomer, thoughonly one anomer is drawn for each compound in the table.

TABLE 2

Compounds of Formula (K)

In another aspect, the invention provides a nitro sugar, which may be anintermediate in the preparation of a desosamine or mycaminose analog. Incertain embodiments, the nitro sugar is a compound of Formula (K):

or salt thereof, wherein:

-   -   R^(1b) is —N(R^(S))₂, —NR^(S)(OR^(S)), or of formula:

-   -   each of R^(2b) and R^(3b) is independently hydrogen, halogen,        optionally substituted C₁-C₆ alkyl, or —OR^(SO).    -   X^(S) is a bond, —C(═O)—, —C(═NR^(SN))—, —S(═O)—, or —S(═O)₂—;    -   L^(S2) is a bond, —NR^(S)—, —O—, or —S—, or a linking group        selected from the group consisting of optionally substituted        alkylene, optionally substituted alkenylene, optionally        substituted alkynylene, optionally substituted heteroalkylene,        optionally substituted heteroalkenylene, and optionally        substituted heteroalkynylene, and combinations thereof;    -   each R^(S) is independently hydrogen, optionally substituted        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted carbocyclyl, optionally        substituted heterocyclyl, optionally substituted aryl,        optionally substituted heteroaryl, an oxygen protecting group        when attached to an oxygen atom, a nitrogen protecting group        when attached to a nitrogen atom, or a sulfur protecting group        when attached to a sulfur atom, or two R^(S) attached to the        same nitrogen atom are taken together to form ═N₂ or an        optionally substituted heterocyclyl or heteroaryl ring;    -   R^(SN) is hydrogen, optionally substituted alkyl, or a nitrogen        protecting group; each of R^(4a) and R^(4b) is independently        hydrogen, optionally substituted C₁-C₆ alkyl, or —OR^(SO); and    -   each of R⁵, R⁶ and R^(SO) is independently hydrogen, halogen,        optionally substituted C₁-C₆ alkyl, a carbohydrate, or an oxygen        protecting group.

In certain embodiments, R^(1b) is not:

In certain embodiments, a compound of Formula (J) is a compound listedin Table 3. The invention contemplates both α and β anomer, though onlyone anomer is drawn for each compound in the table.

TABLE 3

Additional Formulae

In certain embodiments, a compound of Formula (D′) is of Formula (D-1′):

or salt thereof, wherein R¹, R², R³, R^(4a), R^(4b), R⁵, R⁶, R⁷, and R⁸are as defined herein.

In certain embodiments, a compound of Formula (D′) is of Formula (D-2′):

or salt thereof, wherein R¹, R², R³, R^(4a), R^(4b), R⁵, R⁶, R⁷, and R⁸are as defined herein.

In certain embodiments, a compound of Formula (D′) is of Formula(D-d-1′):

or salt thereof, wherein R¹, R², R⁵, R⁶, R⁷, and R⁸ are as definedherein.

In certain embodiments, a compound of Formula (D′) is of Formula(D-d-1′):

or salt thereof, wherein R¹, R², R^(SO), R⁵, R⁶, R⁷, and R⁸ are asdefined herein.

In certain embodiments, a compound of Formula (D′) is of Formula(D-d-1′-A):

or salt thereof, wherein R¹, R², R^(SO), R⁵, R⁶, R⁷, and R⁸ are asdefined herein.

In certain embodiments, a compound of Formula (J) is of Formula (J-1):

or salt thereof, wherein R^(1a), R^(2a), R^(3a), R^(4a), R^(4b), R⁵, R⁶,R^(7a), and R^(8a) are as defined herein.

In certain embodiments, a compound of Formula (J) is of Formula (J-2):

or salt thereof, wherein R^(1a), R^(2a), R^(3a), R^(4a), R^(4b), R⁵, R⁶,R^(7a), and R^(8a) are as defined herein.

In certain embodiments, a compound of Formula (J) is of Formula (J-d-1):

or salt thereof, wherein R^(1a), R^(2a), R⁵, R⁶, R^(7a), and R^(8a) areas defined herein.

In certain embodiments, a compound of Formula (J) is of Formula (J-m-1):

or salt thereof, wherein R^(1a), R^(2a), R^(SO), R⁵, R⁶, R^(7a), andR^(8a) are as defined herein.

In certain embodiments, a compound of Formula (J) is of Formula(J-m-1-A):

or salt thereof, wherein R^(1a), R^(2a), R^(S), R⁵, R⁶, R^(7a), andR^(8a) are as defined herein.

In certain embodiments, a compound of Formula (K) is of Formula (K-1):

or salt thereof, wherein R^(1b), R^(2b), R^(3b), R^(4a), R^(4b), R⁵, andR⁶ are as defined herein.

In certain embodiments, a compound of Formula (K) is of Formula (K-2):

or salt thereof, wherein R^(1b), R^(2b), R^(3b), R^(4a), R^(4b), R⁵, andR⁶ are as defined herein.

In certain embodiments, a compound of Formula (K) is of Formula (K-d-1):

or salt thereof, wherein R^(1b), R^(2b), R⁵, and R⁶ are as definedherein.

In certain embodiments, a compound of Formula (K) is of Formula (K-m-1):

or salt thereof, wherein R^(1b), R^(2b), R^(SO), R⁵, and R⁶ are asdefined herein.

In certain embodiments, a compound of Formula (K) is of Formula(K-m-1-A):

or salt thereof, wherein R^(1b), R^(2b), R^(SO), R⁵, and R⁶ are asdefined herein.Group R¹

Compounds of Formula (A), (B), (B′), (C′), (D′), (Q), and (R) includeR¹, which may be hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, —OR^(S),—N(R^(S))₂, —NR^(S)(OR^(S)), —SR^(S), —SSR^(S), —Si(R^(S))₃,—OSi(R^(S))₃, or of formula:

wherein R^(S), L^(S1), X^(S), L^(S2) are as defined for compounds ofFormula (D′). In certain embodiments, R¹ is hydrogen, halogen,optionally substituted alkyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —OR^(S), —N(R^(S))₂, or of Formula(L^(S)-i). In certain embodiments, R¹ is hydrogen, optionallysubstituted alkyl, —OR^(S), —N(R^(S))₂, or of Formula (L^(S)-i). In someembodiments, R¹ is hydrogen. In some embodiments, R¹ is —F. In someembodiments, R¹ is —Cl, —Br, or —I. In some embodiments, R¹ isoptionally substituted alkyl. In some embodiments, R¹ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R¹ is C₁-C₆ alkyl. In someembodiments, R¹ is methyl. In some embodiments, R¹ is ethyl, propyl, orbutyl. In some embodiments, R¹ is optionally substituted carbocyclyl. Insome embodiments, R¹ is optionally substituted heterocyclyl. In someembodiments, R¹ is optionally substituted aryl. In some embodiments, R¹is optionally substituted phenyl. In some embodiments, R¹ is optionallysubstituted heteroaryl. In some embodiments, R¹ is optionallysubstituted alkenyl. In some embodiments, R¹ is optionally substitutedalkynyl. In some embodiments, R¹ is —NR^(S)(OR^(S)). In someembodiments, R¹ is optionally substituted —SR^(S). In some embodiments,R¹ is optionally substituted —SSR^(S). In some embodiments, R¹ isoptionally substituted —Si(R^(S))₃. In some embodiments, R¹ isoptionally substituted —Si(OR^(S)).

R¹ may be is —OR. In some embodiments, R¹ is hydrogen. In someembodiments, R^(S) is optionally substituted alkyl. In some embodiments,R^(S) is optionally substituted C₁-C₆ alkyl. In some embodiments, R^(S)is C₁-C₆ alkyl. In some embodiments, R^(S) is methyl. In someembodiments, R^(S) is ethyl. In some embodiments, R^(S) is propyl. Insome embodiments, R^(S) is optionally substituted alkenyl. In someembodiments, R^(S) is optionally substituted alkynyl. In someembodiments, R^(S) is optionally substituted carbocyclyl. In someembodiments, R^(S) is optionally substituted heterocyclyl. In someembodiments, R^(S) is optionally substituted aryl. In some embodiments,R^(S) is optionally substituted phenyl. In some embodiments, R^(S) isoptionally substituted heteroaryl. In certain embodiments, R^(S) is anoxygen protecting group. In some embodiments, R^(S) is alkoxycarbonyl.In some embodiments, R^(S) is methoxycarbonyl. In some embodiments,R^(S) is acetyl, benzoyl, benzyl, methoxymethyl ether, p-methoxybenzylether, methylthiomethylether, pivaloyl, tetrahydropyranyl,tetrahydrofuranyl, triphenylmethyl, or silyl (e.g., trimethyl silyl,tert-butyldimethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl).In certain embodiments, R^(S) is a carbohydrate. In certain embodiments,R^(S) is a monosaccharide.

In certain embodiments, R¹ is:

R¹ may be —N(R^(S))₂. The R^(S) groups of —N(R^(S))₂ may be the same ordifferent. In certain embodiments, R¹ is NHR^(S). In certainembodiments, R¹ is —NMeR^(S). In some embodiments, R¹ is —NH₂. In someembodiments, at least one R¹ is optionally substituted alkyl. In someembodiments, at least one R^(S) is optionally substituted C₁-C₆ alkyl.In some embodiments, at least one R^(S) is C₁-C₆ alkyl. In someembodiments, at least one R^(S) is ethyl. In some embodiments, at leastone R^(S) is propyl. In some embodiments, R^(S) is optionallysubstituted alkenyl. In some embodiments, R^(S) is optionallysubstituted alkynyl. In some embodiments, at least one R^(S) isoptionally substituted carbocyclyl. In some embodiments, at least oneR^(S) is optionally substituted heterocyclyl. In some embodiments, atleast one R^(S) is optionally substituted aryl. In some embodiments, atleast one R^(S) is optionally substituted phenyl. In some embodiments,at least one R^(S) is optionally substituted heteroaryl. In certainembodiments, at least one R^(S) is a nitrogen protecting group. In someembodiments, at least one R^(S) is benzyl. In some embodiments, at leastone R^(S) is alkoxycarbonyl. In some embodiments, at least one R^(S) ismethoxycarbonyl or tert-butoxycarbonyl. In some embodiments, at leastone R^(S) is carbobenzyloxy, fluorophenylmethyloxycarbonyl, acetyl,benzoyl, p-toluenesulfonyl, p-bromobenzenesulfonyl,2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, ortrifluoromethanesulfonyl. In certain embodiments, two R^(S) attached tothe same nitrogen atom are taken together to form ═N₂, i.e. —N(R^(S))₂is —N₃. In certain embodiments, two R^(S) attached to the same nitrogenatom are joined to form an optionally substituted heterocyclyl ring. Incertain embodiments, two R^(S) attached to the same nitrogen atom arejoined to form an optionally substituted heteroaryl ring.

In certain embodiments R¹ is:

In certain embodiments, R¹ is of the formula:

In certain embodiments, L^(S1) is a bond. In certain embodiments, L^(S1)is —NR^(S)—. In some embodiments, L^(S1) is —NH—. In certainembodiments, L^(S1) is —O—. In certain embodiments, L^(S1) is —S—. Incertain embodiments, L^(S1) is optionally substituted alkylene. Incertain embodiments, L^(S1) is optionally substituted alkenylene. Incertain embodiments, L^(S1) is optionally substituted alkynylene. Incertain embodiments, L^(S1) is optionally substituted heteroalkylene. Incertain embodiments, L^(S1) is optionally substituted heteroalkenylene.In certain embodiments, L^(S1) is optionally substitutedheteroalkynylene. In certain embodiments, L^(S2) is a bond. In certainembodiments, L^(S2) is —NR^(S)—. In some embodiments, L^(S2) is —NH—. Incertain embodiments, L^(S2) is —O—. In certain embodiments, L^(S2) is—S—. In certain embodiments, L^(S2) is optionally substituted alkylene.In certain embodiments, L^(S2) is optionally substituted alkenylene. Incertain embodiments, L^(S2) is optionally substituted alkynylene. Incertain embodiments, L^(S2) is optionally substituted heteroalkylene. Incertain embodiments, L^(S2) is optionally substituted heteroalkenylene.In certain embodiments, L^(S2) is optionally substitutedheteroalkynylene. In certain embodiments, X^(S) is —C(═O)—. In certainembodiments, X^(S) is —C(═NR^(SN)). In some embodiments, X^(S) is—C(═NH)—. In certain embodiments, X^(S) is —S(═O)—. In certainembodiments, X^(S) is —S(═O)₂—. In some embodiments, at least one R^(S)is optionally substituted alkyl. In some embodiments, at least one R^(S)is optionally substituted C₁-C₆ alkyl. In some embodiments, at least oneR^(S) is C₁-C₆ alkyl. In some embodiments, at least one R^(S) is ethyl.In some embodiments, at least one R^(S) is propyl. In some embodiments,R^(S) is optionally substituted alkenyl. In some embodiments, R isoptionally substituted alkynyl. In some embodiments, at least one R^(S)is optionally substituted carbocyclyl. In some embodiments, at least oneR^(S) is optionally substituted heterocyclyl. In some embodiments, atleast one R^(S) is optionally substituted aryl. In some embodiments, atleast one R^(S) is optionally substituted phenyl. In some embodiments,at least one R^(S) is optionally substituted heteroaryl. In certainembodiments, at least one R^(S) is a nitrogen protecting group. In someembodiments, at least one R^(S) is benzyl. In some embodiments, at leastone R^(S) is alkoxycarbonyl. In some embodiments, at least one R^(S) ismethoxycarbonyl or tert-butoxycarbonyl. In some embodiments, at leastone R^(S) is carbobenzyloxy, fluorophenylmethyloxycarbonyl, acetyl,benzoyl, p-toluenesulfonyl, p-bromobenzenesulfonyl chloride,2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, ortrifluoromethanesulfonyl. In certain embodiments, R^(S) is an oxygenprotecting group. In some embodiments, R^(S) is alkoxycarbonyl. In someembodiments, R^(S) is methoxycarbonyl. In some embodiments, R^(S) isacetyl, benzoyl, benzyl, methoxymethyl ether, p-methoxybenzyl ether,methylthiomethylether, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl,triphenylmethyl, or silyl (e.g., trimethyl silyl,tert-butyldimethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl).

In certain embodiments, R¹ is —NHC(═O)R^(S), —NHC(═O)OR^(S), or—NHC(═O)N(R^(S))₂. In certain embodiments, R¹ is:

In certain embodiments, R¹ is —NHC(═NR^(SN))R^(S), —NHC(═NR^(SN))OR^(S),or —NHC(═NR^(SN))N(R^(S))₂. In certain embodiments, R¹ is:

In certain embodiments, R¹ is —NHS(═O)₂R^(S) In certain embodiments, R¹is:

Group R^(1a)

Compounds of Formula (J) include R^(1a), which may be —N(R^(S))₂,—NR^(S)(OR^(S)), or of formula:

wherein R^(S), X^(S), and L^(S2) are as defined for compounds of Formula(J). In some embodiments, R^(1a) is —NR^(S)(OR^(S)). R^(1a) may be—N(R^(S))₂. The R^(S) groups of —N(R^(S))₂ may be the same or different.In certain embodiments, R^(1a) is —NHR^(S). In certain embodiments,R^(1a) is —NMeR^(S). In some embodiments, R^(1a) is —NH₂. In someembodiments, at least one R^(S) is optionally substituted alkyl. In someembodiments, at least one R^(S) is optionally substituted C₁-C₆ alkyl.In some embodiments, at least one R^(S) is C₁-C₆ alkyl. In someembodiments, at least one R^(S) is ethyl. In some embodiments, at leastone R^(S) is propyl. In some embodiments, R^(S) is optionallysubstituted alkenyl. In some embodiments, R^(S) is optionallysubstituted alkynyl. In some embodiments, at least one R^(S) isoptionally substituted carbocyclyl. In some embodiments, at least oneR^(S) is optionally substituted heterocyclyl. In some embodiments, atleast one R^(S) is optionally substituted aryl. In some embodiments, atleast one R^(S) is optionally substituted phenyl. In some embodiments,at least one R^(S) is optionally substituted heteroaryl. In certainembodiments, at least one R^(S) is a nitrogen protecting group. In someembodiments, at least one R^(S) is benzyl. In some embodiments, at leastone R^(S) is alkoxycarbonyl. In some embodiments, at least one R^(S) ismethoxycarbonyl or tert-butoxycarbonyl. In some embodiments, at leastone R^(S) is carbobenzyloxy, fluorophenylmethyloxycarbonyl, acetyl,benzoyl, p-toluenesulfonyl, p-bromobenzenesulfonyl,2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, ortrifluoromethanesulfonyl. In certain embodiments, two R^(S) attached tothe same nitrogen atom are taken together to form ═N₂, i.e. —N(R^(S))₂is —N₃. In certain embodiments, two R^(S) attached to the same nitrogenatom are joined to form an optionally substituted heterocyclyl ring. Incertain embodiments, two R^(S) attached to the same nitrogen atom arejoined to form an optionally substituted heteroaryl ring. In certainembodiments R^(1a) is:

R^(1a) may be of formula:

In certain embodiments, L^(S2) is a bond. In certain embodiments, L^(S2)is —NR^(S)—. In some embodiments, L^(S2) is —NH—. In certainembodiments, L^(S2) is —O—. In certain embodiments, L^(S2) is —S—. Incertain embodiments, L^(S2) is optionally substituted alkylene. Incertain embodiments, L^(S2) is optionally substituted alkenylene. Incertain embodiments, L^(S2) is optionally substituted alkynylene. Incertain embodiments, L^(S2) is optionally substituted heteroalkylene. Incertain embodiments, L^(S2) is optionally substituted heteroalkenylene.In certain embodiments, L^(S2) is optionally substitutedheteroalkynylene. In certain embodiments, X^(S) is —C(═O)—. In certainembodiments, X^(S) is —C(═NR^(SN))—. In some embodiments, X^(S) is—C(═NH)—. In certain embodiments, X^(S) is —S(═O)—. In certainembodiments, X^(S) is —S(═O)₂—. In some embodiments, at least one R^(S)is optionally substituted alkyl. In some embodiments, at least one R^(S)is optionally substituted C₁-C₆ alkyl. In some embodiments, at least oneR^(S) is C₁-C₆ alkyl. In some embodiments, at least one R^(S) is ethyl.In some embodiments, at least one R^(S) is propyl. In some embodiments,R^(S) is optionally substituted alkenyl. In some embodiments, R^(S) isoptionally substituted alkynyl. In some embodiments, at least one R^(S)is optionally substituted carbocyclyl. In some embodiments, at least oneR^(S) is optionally substituted heterocyclyl. In some embodiments, atleast one R^(S) is optionally substituted aryl. In some embodiments, atleast one R^(S) is optionally substituted phenyl. In some embodiments,at least one R^(S) is optionally substituted heteroaryl. In certainembodiments, at least one R^(S) is a nitrogen protecting group. In someembodiments, at least one R^(S) is benzyl. In some embodiments, at leastone R^(S) is alkoxycarbonyl. In some embodiments, at least one R^(S) ismethoxycarbonyl or tert-butoxycarbonyl. In some embodiments, at leastone R^(S) is carbobenzyloxy, fluorophenylmethyloxycarbonyl, acetyl,benzoyl, p-toluenesulfonyl, p-bromobenzenesulfonyl chloride,2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, ortrifluoromethanesulfonyl. In certain embodiments, R^(S) is an oxygenprotecting group. In some embodiments, R^(S) is alkoxycarbonyl. In someembodiments, R^(S) is methoxycarbonyl. In some embodiments, R^(S) isacetyl, benzoyl, benzyl, methoxymethyl ether, p-methoxybenzyl ether,methylthiomethylether, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl,triphenylmethyl, or silyl (e.g., trimethyl silyl,tert-butyldimethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl).

In certain embodiments, R^(1a) is —NHC(═O)R^(S), —NHC(═O)OR^(S), or—NHC(═O)N(R^(S))₂. In certain embodiments, R^(1a) is:

In certain embodiments, R^(1a) is —NHC(═NR^(SN))R^(S),—NHC(═NR^(SN))OR^(S), or —NHC(═NR^(SN))N(R^(S))₂. In certainembodiments, R^(1a) is:

In certain embodiments, R^(1a) is —NHS(═O)₂R^(S). In certainembodiments, R^(1a) is:

Group R^(1b)

Compounds of Formula (J) include R^(1b), which may be —N(R^(S))₂,—NR^(S)(OR^(S)), or of formula:

wherein R^(S), X^(S), are L^(S2) are as defined for compounds of Formula(J). In some embodiments, R^(1b) is —NR^(S)(OR^(S)). R^(1b) may be—N(R^(S))₂. The R^(S) groups of —N(R^(S))₂ may be the same or different.In certain embodiments, R^(1b) is NHR^(S). In certain embodiments,R^(1b) is —NMeR^(S). In some embodiments, R^(1b) is —NH₂. In someembodiments, at least one R^(S) is optionally substituted alkyl. In someembodiments, at least one R^(S) is optionally substituted C₁-C₆ alkyl.In some embodiments, at least one R^(S) is C₁-C₆ alkyl. In someembodiments, at least one R^(S) is ethyl. In some embodiments, at leastone R^(S) is propyl. In some embodiments, R^(S) is optionallysubstituted alkenyl. In some embodiments, R^(S) is optionallysubstituted alkynyl. In some embodiments, at least one R^(S) isoptionally substituted carbocyclyl. In some embodiments, at least oneR^(S) is optionally substituted heterocyclyl. In some embodiments, atleast one R^(S) is optionally substituted aryl. In some embodiments, atleast one R^(S) is optionally substituted phenyl. In some embodiments,at least one R^(S) is optionally substituted heteroaryl. In certainembodiments, at least one R^(S) is a nitrogen protecting group. In someembodiments, at least one R^(S) is benzyl. In some embodiments, at leastone R^(S) is alkoxycarbonyl. In some embodiments, at least one R^(S) ismethoxycarbonyl or tert-butoxycarbonyl. In some embodiments, at leastone R^(S) is carbobenzyloxy, fluorophenylmethyloxycarbonyl, acetyl,benzoyl, p-toluenesulfonyl, p-bromobenzenesulfonyl,2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, ortrifluoromethanesulfonyl. In certain embodiments, two R^(S) attached tothe same nitrogen atom are taken together to form ═N₂, i.e. —N(R^(S))₂is —N₃. In certain embodiments, two R^(S) attached to the same nitrogenatom are joined to form an optionally substituted heterocyclyl ring. Incertain embodiments, two R^(S) attached to the same nitrogen atom arejoined to form an optionally substituted heteroaryl ring. In certainembodiments R^(1b) is:

R^(1b) may be of formula:

In certain embodiments, L^(S2) is a bond. In certain embodiments, L^(S2)is —NR^(S)—. In some embodiments, L^(S2) is —NH—. In certainembodiments, L^(S2) is —O—. In certain embodiments, L^(S2) is —S—. Incertain embodiments, L^(S2) is optionally substituted alkylene. Incertain embodiments, L^(S2) is optionally substituted alkenylene. Incertain embodiments, L^(S2) is optionally substituted alkynylene. Incertain embodiments, L^(S2) is optionally substituted heteroalkylene. Incertain embodiments, L^(S2) is optionally substituted heteroalkenylene.In certain embodiments, L^(S2) is optionally substitutedheteroalkynylene. In certain embodiments, X^(S) is —C(═O)—. In certainembodiments, X^(S) is —C(═NR^(SN))—. In some embodiments, X^(S) is—C(═NH)—. In certain embodiments, X^(S) is —S(═O)—. In certainembodiments, X^(S) is —S(═O)₂—. In some embodiments, at least one R^(S)is optionally substituted alkyl. In some embodiments, at least one R^(S)is optionally substituted C₁-C₆ alkyl. In some embodiments, at least oneR^(S) is C₁-C₆ alkyl. In some embodiments, at least one R^(S) is ethyl.In some embodiments, at least one R^(S) is propyl. In some embodiments,R^(S) is optionally substituted alkenyl. In some embodiments, R^(S) isoptionally substituted alkynyl. In some embodiments, at least one R^(S)is optionally substituted carbocyclyl. In some embodiments, at least oneR^(S) is optionally substituted heterocyclyl. In some embodiments, atleast one R^(S) is optionally substituted aryl. In some embodiments, atleast one R^(S) is optionally substituted phenyl. In some embodiments,at least one R^(S) is optionally substituted heteroaryl. In certainembodiments, at least one R^(S) is a nitrogen protecting group. In someembodiments, at least one R^(S) is benzyl. In some embodiments, at leastone R^(S) is alkoxycarbonyl. In some embodiments, at least one R^(S) ismethoxycarbonyl or tert-butoxycarbonyl. In some embodiments, at leastone R^(S) is carbobenzyloxy, fluorophenylmethyloxycarbonyl, acetyl,benzoyl, p-toluenesulfonyl, p-bromobenzenesulfonyl chloride,2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, ortrifluoromethanesulfonyl. In certain embodiments, R^(S) is an oxygenprotecting group. In some embodiments, R^(S) is alkoxycarbonyl. In someembodiments, R^(S) is methoxycarbonyl. In some embodiments, R^(S) isacetyl, benzoyl, benzyl, methoxymethyl ether, p-methoxybenzyl ether,methylthiomethylether, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl,triphenylmethyl, or silyl (e.g., trimethyl silyl,tert-butyldimethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl).

In certain embodiments, R^(1b) is —NHC(═O)R^(S), —NHC(═O)OR^(S), or—NHC(═O)N(R^(S))₂. In certain embodiments, R^(1b) is:

In certain embodiments, R^(1b) is —NHC(═NR^(SN))R^(S),—NHC(═NR^(SN))OR^(S), or —NHC(═NR^(SN))N(R^(S))₂. In certainembodiments, R^(1b) is

In certain embodiments, —NHS(═O)₂R^(S) In certain embodiments, R^(1b)is:

Groups R² and R³

Compounds of Formulae (A), (B), (B′), (C′), (D′), (Q), and (R) includeR² and R³, which each may independently be hydrogen, halogen, optionallysubstituted C₁-C₆ alkyl, —R^(SO), or —N(R^(SN))₂. In certainembodiments, R² and R³ are both hydrogen. In certain embodiments, atleast one of R² and R³ is hydrogen. In some embodiments, R² is hydrogen.In some embodiments, R² is optionally substituted C₁-C₆ alkyl. In someembodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is methyl. Insome embodiments, R² is ethyl, propyl, or butyl. In some embodiments, R²is —F. In some embodiments, R² is —Cl, —Br, or —I. In certainembodiments, R² is —OR^(SO). In some embodiments, R² is —OH. In someembodiments, R² is methoxy, ethoxy, propoxy, or butoxy. In someembodiments, R² is —OR^(SO), and R^(SO) is an oxygen protecting group(e.g., alkoxycarbonyl). In certain embodiments R² is —N(R^(SN))₂In someembodiments, R² is —NHR^(SN). In some embodiments, R² is —NH₂. In someembodiments, R² is —NHMe or —NMe₂. In some embodiments, R² is —NHR^(SN),and R^(SN) is a nitrogen protecting group. In some embodiments, R³ ishydrogen. In some embodiments, R³ is optionally substituted C₁-C₆ alkyl.In some embodiments, R³ is C₁-C₆ alkyl. In some embodiments, R³ ismethyl. In some embodiments, R³ is ethyl, propyl, or butyl. In someembodiments, R³ is —F. In some embodiments, R³ is —Cl, —Br, or —I. Incertain embodiments, R³ is —OR^(SO). In some embodiments, R³ is —OH. Insome embodiments, R³ is methoxy, ethoxy, propoxy, or butoxy. In someembodiments, R³ is —OR^(SO), and R^(SO) is an oxygen protecting group(e.g., alkoxycarbonyl). In certain embodiments R³ is —N(R^(SN))₂. Insome embodiments, R³ is —NHR^(SN). In some embodiments, R³ is —NH₂. Insome embodiments, R³ is —NHMe or —NMe₂. In some embodiments, R³ is—NHR^(SN), and RN is a nitrogen protecting group.

Groups R^(2a) and R^(3a)

Compounds of Formula (J) include R^(2a) and R^(3a), which each mayindependently be hydrogen, halogen, optionally substituted C₁-C₆ alkyl,or —OR^(SO). In certain embodiments, R^(2a) and R^(3a) are hydrogen. Incertain embodiments, at least one of R^(2a) and R^(3a) is hydrogen. Insome embodiments, R^(2a) is hydrogen. In some embodiments, R^(2a) isoptionally substituted C₁-C₆ alkyl. In some embodiments, R^(2a) is C₁-C₆alkyl. In some embodiments, R^(2a) is methyl. In some embodiments,R^(2a) is ethyl, propyl, or butyl. In some embodiments, R^(2a) is —F. Insome embodiments, R^(2a) is —Cl, —Br, or —I. In certain embodiments,R^(2a) is —OR^(SO). In some embodiments, R^(2a) is —OH. In someembodiments, R^(2a) is methoxy, ethoxy, propoxy, or butoxy. In someembodiments, R^(2a) is —OR^(SO), and R^(SO) is an oxygen protectinggroup (e.g., alkoxycarbonyl). In some embodiments, R^(3a) is hydrogen.In some embodiments, R^(3a) is optionally substituted C₁-C₆ alkyl. Insome embodiments, R^(3a) is C₁-C₆ alkyl. In some embodiments, R^(3a) ismethyl. In some embodiments, R^(3a) is ethyl, propyl, or butyl. In someembodiments, R^(3a) is —F. In some embodiments, R^(3a) is —Cl, —Br, or—I. In certain embodiments, R^(3a) is —OR^(SO). In some embodiments,R^(3a) is —OH. In some embodiments, R^(3a) is methoxy, ethoxy, propoxy,or butoxy. In some embodiments, R^(3a) is —OR^(SO), and R^(SO) is anoxygen protecting group (e.g., alkoxycarbonyl).

Groups R^(2b) and R^(3b)

Compounds of Formula (K) include R^(2b) and R^(3b), which each mayindependently be hydrogen, halogen, optionally substituted C₁-C₆ alkyl,—OR^(SO). In certain embodiments, R^(2b) and R^(3b) are hydrogen. Incertain embodiments, at least one of R^(2b) and R^(3b) is hydrogen. Insome embodiments, R^(2b) is hydrogen. In some embodiments, R^(2b) isoptionally substituted C₁-C₆ alkyl. In some embodiments, R^(2b) is C₁-C₆alkyl. In some embodiments, R^(2b) is methyl. In some embodiments,R^(2b) is ethyl, propyl, or butyl. In some embodiments, R^(2b) is —F. Insome embodiments, R^(2b) is —Cl, —Br, or —I. In certain embodiments,R^(2b) is —OR^(SO). In some embodiments, R^(2b) is —OH. In someembodiments, R^(2b) is methoxy, ethoxy, propoxy, or butoxy. In someembodiments, R^(2b) is —OR^(SO), and R^(SO) is an oxygen protectinggroup (e.g., alkoxycarbonyl). In some embodiments, R^(3b) is hydrogen.In some embodiments, R^(3b) is optionally substituted C₁-C₆ alkyl. Insome embodiments, R^(3b) is C₁-C₆ alkyl. In some embodiments, R^(3b) ismethyl. In some embodiments, R^(3b) is ethyl, propyl, or butyl. In someembodiments, R^(3b) is —F. In some embodiments, R^(3b) is —Cl, —Br, or—I. In certain embodiments, R^(3b) is —OR^(SO). In some embodiments,R^(3b) is —OH. In some embodiments, R^(3b) is methoxy, ethoxy, propoxy,or butoxy. In some embodiments, R^(3b) is —OR^(SO), and R^(SO) is anoxygen protecting group (e.g., alkoxycarbonyl).

Groups R^(4a) and R^(4b)

Compounds of Formulae (A), (B), (B′), (C′), (D′), (J), (K), and (Q)include R^(4a) and R^(4b), which each may independently be hydrogen,halogen, optionally substituted C₁-C₆ alkyl, or —OR^(SO). Compounds ofFormula (R) also include group R^(4a). In certain embodiments, R^(4a)and R³ are hydrogen. In certain embodiments, at least one of R^(4a) andR³ is hydrogen. In some embodiments, R^(4a) is hydrogen. In someembodiments, R^(4a) is optionally substituted C₁-C₆ alkyl. In someembodiments, R^(4a) is C₁-C₆ alkyl. In some embodiments, R^(4a) ismethyl. In some embodiments, R^(4a) is ethyl, propyl, or butyl. In someembodiments, R^(4a) is —F. In some embodiments, R^(4a) is —Cl, —Br, or—I. In certain embodiments, R^(4a) is —OR^(SO). In some embodiments,R^(4a) is —OH. In some embodiments, R^(4a) is methoxy, ethoxy, propoxy,or butoxy. In some embodiments, R^(4b) is —OR^(SO), and R^(SO) is anoxygen protecting group (e.g., alkoxycarbonyl). In some embodiments,R^(4a) is —OR^(SO), and R^(SO) is a carbohydrate. In some embodiments,R^(4b) is —OR^(SO), and R^(SO) is a monosaccharide. In some embodiments,R^(4b) is hydrogen. In some embodiments, R^(4b) is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R^(4b) is C₁-C₆ alkyl. Insome embodiments, R^(4b) is methyl. In some embodiments, R^(4b) isethyl, propyl, or butyl. In some embodiments, R^(4b) is —F. In someembodiments, R^(4b) is —Cl, —Br, or —I. In certain embodiments, R^(4b)is —OR^(SO). In some embodiments, R^(4b) is —OH. In some embodiments,R^(4b) is methoxy, ethoxy, propoxy, or butoxy. In some embodiments,R^(4b) is —OR^(SO), and R^(SO) is an oxygen protecting group (e.g.,alkoxycarbonyl). In some embodiments, R^(4b) is —OR^(SO), and R^(SO) isa carbohydrate. In some embodiments, R^(4b) is —OR^(SO), and R^(SO) is amonosaccharide.

Groups R⁵ and R⁶

Compounds of Formula (B′), (C′), (D′), (J), and (K) include R⁵ and R⁶,which each may independently be hydrogen, optionally substituted C₁-C₆alkyl, a carbohydrate, or an oxygen protecting group. In certainembodiments, R⁵ and R⁶ are hydrogen. In certain embodiments, at leastone of R⁵ and R⁶ is hydrogen. In certain embodiments, R⁵ and R⁶ are bothoxygen protecting groups. In certain embodiments, R⁵ and R⁶ are bothidentical oxygen protecting groups. In some embodiments, R⁵ is hydrogen.In some embodiments, R⁵ is optionally substituted C₁-C₆ alkyl. In someembodiments, R⁵ is C₁-C₆ alkyl. In some embodiments, R⁵ is methyl. Insome embodiments, R⁵ is ethyl, propyl, or butyl. In certain embodiments,R⁵ is an oxygen protecting group. In some embodiments, R⁵ isalkoxycarbonyl. In some embodiments, R⁵ is methoxycarbonyl. In someembodiments, R⁵ is acetyl, benzoyl, benzyl, methoxymethyl ether,p-methoxybenzyl ether, methylthiomethylether, pivaloyl,tetrahydropyranyl, tetrahydrofuranyl, triphenylmethyl, or silyl (e.g.,trimethyl silyl, tert-butyldimethylsilyl, triisopropylsilyloxymethyl,triisopropylsilyl). In some embodiments, R⁵ is a carbohydrate. In someembodiments, R⁵ is a monosaccharide. In some embodiments, R⁶ ishydrogen. In some embodiments, R⁶ is optionally substituted C₁-C₆ alkyl.In some embodiments, R⁶ is C₁-C₆ alkyl. In some embodiments, R⁶ ismethyl. In some embodiments, R⁶ is ethyl, propyl, or butyl. In certainembodiments, R⁶ is an oxygen protecting group. In some embodiments, R⁶is alkoxycarbonyl. In some embodiments, R⁶ is methoxycarbonyl. In someembodiments, R⁶ is acetyl, benzoyl, benzyl, methoxymethyl ether,p-methoxybenzyl ether, methylthiomethylether, pivaloyl,tetrahydropyranyl, tetrahydrofuranyl, triphenylmethyl, or silyl (e.g.,trimethyl silyl, tert-butyldimethylsilyl, triisopropylsilyloxymethyl,triisopropylsilyl). In some embodiments, R⁶ is a carbohydrate. In someembodiments, R⁶ is a monosaccharide.

Groups R⁷ and R⁸

Compounds of Formula (D′) include R⁷ and R⁸, which each mayindependently be hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group, or R⁷ andR⁸ may be joined to form an optionally substituted heterocyclyl orheteroaryl ring. In certain embodiments, R⁷ and R⁸ are eachindependently hydrogen, optionally substituted C₁-C₆ alkyl, or anitrogen protecting group, or R⁷ and R⁸ may be joined to form anoptionally substituted heterocyclyl or heteroaryl ring. In certainembodiments, at least one of R⁷ and R⁸ is hydrogen. In certainembodiments, R⁷ and R⁸ are joined to form an optionally substitutedheterocyclyl ring. In certain embodiments, R⁷ and R⁸ are joined to forman optionally substituted heteroaryl ring. In certain embodiments, R⁷and R⁸ are optionally substituted C₁-C₆ alkyl. In certain embodiments,R⁷ and R⁸ are C₁-C₆ alkyl. In certain embodiments, R⁷ and R⁸ are methyl.In certain embodiments, R⁷ and R⁸ are both ethyl, both propyl, or bothbutyl. In certain embodiments, R⁷ and R⁸ are independently methyl,propyl, or butyl. In certain embodiments, R⁷ and R⁸ are both nitrogenprotecting groups. In certain embodiments, R⁷ and R⁸ are both identicalnitrogen protecting groups. In certain embodiments, R⁷ is hydrogen, andR⁸ is optionally substituted C₁-C₆ alkyl. In certain embodiments, R⁷ ishydrogen, and R⁸ is C₁-C₆ alkyl. In certain embodiments, R⁷ is hydrogen,and R⁸ is methyl. In certain embodiments, R⁷ is hydrogen, and R⁸ isethyl, propyl, or butyl. In certain embodiments, R⁷ is hydrogen, and R⁸is a nitrogen protecting group. In certain embodiments, R⁷ is hydrogen,and R⁸ is benzyl. In certain embodiments, R⁷ is hydrogen, and R⁸ isalkoxycarbonyl (e.g., methoxycarbonyl, tert-butylcarbonyl). In certainembodiments, R⁷ is hydrogen, and R⁸ is carbobenzyloxy,fluorophenylmethyloxycarbonyl, acetyl, benzoyl, p-toluenesulfonyl,p-bromobenzenesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl,methanesulfonyl, or trifluoromethanesulfonyl.

Groups R^(7a) and R^(8a)

Compounds of Formula (J) include R^(7a) and R^(8a), which each mayindependently be hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group, or R^(7a)and R^(8a) may be joined to form an optionally substituted heterocyclylor heteroaryl ring. In certain embodiments, R^(7a) and R^(8a) are eachindependently hydrogen, optionally substituted C₁-C₆ alkyl, or anitrogen protecting group, or R^(7a) and R^(8a) may be joined to form anoptionally substituted heterocyclyl or heteroaryl ring. In certainembodiments, at least one of R^(7a) and R^(8a) is hydrogen. In certainembodiments, R^(7a) and R^(8a) are joined to form an optionallysubstituted heterocyclyl ring. In certain embodiments, R^(7a) and R^(8a)are joined to form an optionally substituted heteroaryl ring. In certainembodiments, R^(7a) and R^(8a) are optionally substituted C₁-C₆ alkyl.In certain embodiments, R^(7a) and R^(8a) are C₁-C₆ alkyl. In certainembodiments, R^(7a) and R^(8a) are methyl. In certain embodiments,R^(7a) and R^(8a) are both ethyl, both propyl, or both butyl. In certainembodiments, R^(7a) and R^(8a) are independently methyl, propyl, orbutyl. In certain embodiments, R^(7a) and R^(8a) are both nitrogenprotecting groups. In certain embodiments, R^(7a) and R^(8a) are bothidentical nitrogen protecting groups. In certain embodiments, R^(7a) ishydrogen, and R^(8a) is optionally substituted C₁-C₆ alkyl. In certainembodiments, R^(7a) is hydrogen, and R^(8a) is C₁-C₆ alkyl. In certainembodiments, R^(7a) is hydrogen, and R^(8a) is methyl. In certainembodiments, R^(7a) is hydrogen, and R^(8a) is ethyl, propyl, or butyl.In certain embodiments, R^(7a) is hydrogen, and R^(8a) is a nitrogenprotecting group. In certain embodiments, R^(7a) is hydrogen, and R^(8a)is benzyl. In certain embodiments, R^(7a) is hydrogen, and R^(8a) isalkoxycarbonyl (e.g., methoxycarbonyl, tert-butylcarbonyl). In certainembodiments, R^(7a) is hydrogen, and R^(8a) is carbobenzyloxy,fluorophenylmethyloxycarbonyl, acetyl, benzoyl, p-toluenesulfonyl,p-bromobenzenesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl,methanesulfonyl, or trifluoromethanesulfonyl.

Groups R^(S), R^(SO), and R^(SN)

Compounds of Formulae (A), (B), (B′), (C′), (D′), (Q), (J), (K), and (R)may include one or more R^(S), which independently may be hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, an oxygen protecting group when attached to anoxygen atom, a nitrogen protecting group when attached to a nitrogenatom, or a sulfur protecting group when attached to a sulfur atom, ortwo R^(S) attached to the same nitrogen atom may be taken together toform ═N₂ or an optionally substituted heterocyclyl or heteroaryl ring.In some embodiments, R^(S) is hydrogen. In some embodiments, R^(S) isoptionally substituted alkyl. In some embodiments, R^(S) is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R^(S) is C₁-C₆ alkyl. Insome embodiments, R^(S) is methyl. In some embodiments, R^(S) is ethyl,propyl, or butyl. In some embodiments, R^(S) is optionally substitutedalkenyl. In some embodiments, R^(S) is optionally substituted alkynyl.In some embodiments, R^(S) is optionally substituted carbocyclyl. Insome embodiments, R^(S) is optionally substituted heterocyclyl. In someembodiments, R^(S) is optionally substituted aryl. In some embodiments,R^(S) is optionally substituted phenyl. In some embodiments, R^(S) isoptionally substituted heteroaryl. In certain embodiments, R^(S) is anoxygen protecting group. In some embodiments, R^(S) is alkoxycarbonyl.In some embodiments, R^(S) is methoxycarbonyl. In some embodiments,R^(S) is acetyl, benzoyl, benzyl, methoxymethyl ether, p-methoxybenzylether, methylthiomethylether, pivaloyl, tetrahydropyranyl,tetrahydrofuranyl, triphenylmethyl, or silyl (e.g., trimethyl silyl,tert-butyldimethylsilyl, triisopropylsilyloxymethyl, triisopropylsilyl).In certain embodiments, R^(S) is a carbohydrate. In certain embodiments,R^(S) is a monosaccharide. In certain embodiments, at least one R^(S) isa nitrogen protecting group. In some embodiments, at least one R^(S) isbenzyl. In some embodiments, at least one R^(S) is alkoxycarbonyl. Insome embodiments, at least one R^(S) is methoxycarbonyl ortert-butoxycarbonyl. In some embodiments, at least one R^(S) iscarbobenzyloxy, fluorophenylmethyloxycarbonyl, acetyl, benzoyl,p-toluenesulfonyl, p-bromobenzenesulfonyl, 2-nitrobenzenesulfonyl,4-nitrobenzenesulfonyl, methanesulfonyl, or trifluoromethanesulfonyl. Incertain embodiments, two R^(S) attached to the same nitrogen atom aretaken together to form ═N₂, i.e. —N(R^(S))₂ is —N₃. In certainembodiments, two R^(S) attached to the same nitrogen atom are joined toform an optionally substituted heterocyclyl ring. In certainembodiments, two R^(S) attached to the same nitrogen atom are joined toform an optionally substituted heteroaryl ring. In certain embodiments,R^(S) is a sulfur protecting group. In certain embodiments, R^(S) isoptionally substituted alkenyl. In certain embodiments, R^(S) isoptionally substituted alkynyl.

Compounds of Formula (A), (B), (B′), (C′), (D′), (Q), and (R) mayinclude one or more R^(SO), which independently may be hydrogen,optionally substituted C₁-C₆ alkyl, a carbohydrate, or an oxygenprotecting group. In some embodiments, R^(SO) is hydrogen. In someembodiments, R^(SO) is optionally substituted C₁-C₆ alkyl. In someembodiments, R^(SO) is C₁-C₆ alkyl. In some embodiments, R^(SO) ismethyl. In some embodiments, R^(SO) is ethyl, propyl, or butyl. Incertain embodiments, R^(SO) is an oxygen protecting group. In someembodiments, R^(SO) is alkoxycarbonyl. In some embodiments, R^(SO) ismethoxycarbonyl. In some embodiments, R^(SO) is acetyl, benzoyl, benzyl,methoxymethyl ether, p-methoxybenzyl ether, methylthiomethylether,pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, triphenylmethyl, orsilyl (e.g., trimethyl silyl, tert-butyldimethylsilyl,triisopropylsilyloxymethyl, triisopropylsilyl). In some embodiments,R^(SO) is a carbohydrate. In some embodiments, R^(SO) is amonosaccharide.

Compounds of Formulae (A), (B), (B′), (C′), (D′), (Q), and (R) mayinclude R^(SO), which may independently be hydrogen, optionallysubstituted C₁-C₆ alkyl, or a nitrogen protecting group, or two R^(SN)attached to the same nitrogen atom may be joined to form an optionallysubstituted heterocyclyl or heteroaryl ring. In certain embodiments,R^(SN) is optionally substituted C₁-C₆ alkyl. In certain embodiments,R^(SN) is C₁-C₆ alkyl. In certain embodiments, R^(SN) is methyl. Incertain embodiments, R^(SN) is ethyl, propyl, or butyl. In certainembodiments, R^(SN) is a nitrogen protecting group. In certainembodiments, R^(SN) is benzyl. In certain embodiments, R^(SN) isalkoxycarbonyl (e.g., methoxycarbonyl, tert-butylcarbonyl). In certainembodiments, R^(SN) is carbobenzyloxy, fluorophenylmethyloxycarbonyl,acetyl, benzoyl, p-toluenesulfonyl, p-bromobenzenesulfonyl,2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, methanesulfonyl, ortrifluoromethanesulfonyl. In certain embodiments, two R^(SN) attached tothe same nitrogen atom are joined to form an optionally substitutedheterocyclyl ring. In certain embodiments, two R^(SN) attached to thesame nitrogen atom are joined to form an optionally substitutedheteroaryl ring.

Definitions

Chemical Terms

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The invention additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

In a formula,

is a single bond where the stereochemistry of the moieties immediatelyattached thereto is not specified,

is absent or a single bond, and

or

is a single or double bond.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, replacement of ¹⁹F with ¹⁸F, or the replacement of a carbon bya ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure.Such compounds are useful, for example, as analytical tools or probes inbiological assays.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclicgroups. Likewise, the term “heteroaliphatic” refers to heteroalkyl,heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, thealkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆alkyl, e.g., —CF₃, Bn).

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkylmoiety has 1 to 8 carbon atoms (“C₁₋₈haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 6 carbon atoms (“C₁₋₆ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C₁₋₄haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbonatoms (“C₁₋₃ haloalkyl”). In some embodiments, the haloalkyl moiety has1 to 2 carbon atoms (“C₁₋₂ haloalkyl”). Examples of haloalkyl groupsinclude —CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

The term “heteroalkyl” refers to an alkyl group, which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry is not specified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

The term “heteroalkenyl” refers to an alkenyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkenylgroup refers to a group having from 2 to 10 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkenyl”). In some embodiments, a heteroalkenyl group has2 to 9 carbon atoms at least one double bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 8 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbonatoms, at least one double bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbonatoms, at least one double bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”).In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, atleast one double bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₈ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

The term “heteroalkynyl” refers to an alkynyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynylgroup refers to a group having from 2 to 10 carbon atoms, at least onetriple bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkynyl”). In some embodiments, a heteroalkynyl group has2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂-salkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbonatoms, at least one triple bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbonatoms, at least one triple bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”).In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, atleast one triple bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl(C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) andcyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) andcyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₄ cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, triazinanyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14 n electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by an aryl group, wherein the point of attachment is on thealkyl moiety.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14 π electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by a heteroaryl group, wherein the point of attachment is onthe alkyl moiety.

The term “unsaturated bond” refers to a double or triple bond.

The term “unsaturated” or “partially unsaturated” refers to a moietythat includes at least one double or triple bond.

The term “saturated” refers to a moiety that does not contain a doubleor triple bond, i.e., the moiety only contains single bonds.

Affixing the suffix “-ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl groups are optionally substituted. “Optionallysubstituted” refers to a group which may be substituted or unsubstituted(e.g., “substituted” or “unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” heteroalkyl, “substituted” or“unsubstituted” heteroalkenyl, “substituted” or “unsubstituted”heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted” means that at least onehydrogen present on a group is replaced with a permissible substituent,e.g., a substituent which upon substitution results in a stablecompound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, and includes any of thesubstituents described herein that results in the formation of a stablecompound. The present invention contemplates any and all suchcombinations in order to arrive at a stable compound. For purposes ofthis invention, heteroatoms such as nitrogen may have hydrogensubstituents and/or any suitable substituent as described herein whichsatisfy the valencies of the heteroatoms and results in the formation ofa stable moiety. The invention is not intended to be limited in anymanner by the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa)—,—SSR^(cc), —C(═O)R^(cc), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa)—, —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(aa)groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—O^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R_(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR—)R^(ff), —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee),—CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂,—OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R⁹groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₂,—N(C₁₋₆alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆alkyl)⁺X⁻, —NH₃ ⁺X⁻,—N(OC₁₋₆alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆alkyl), —NH(OH), —SH, —SC₁₋₆alkyl, —SS(C₁₋₆alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆alkyl), —NHC(O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl),—NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂,—OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R⁹substituents can be joined to form ═O or ═S; wherein X⁻ is a counterion.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R_(aa),—SO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein.

The term “thiol” or “thio” refers to the group —SH. The term“substituted thiol” or “substituted thio,” by extension, refers to athiol group wherein the sulfur atom directly attached to the parentmolecule is substituted with a group other than hydrogen, and includesgroups selected from —SR^(aa), —S═SR^(cc), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa), wherein R^(aa) andR^(cc) are as defined herein.

The term “amino” refers to the group —NH₂. The term “substituted amino,”by extension, refers to a monosubstituted amino, a disubstituted amino,or a trisubstituted amino. In certain embodiments, the “substitutedamino” is a monosubstituted amino or a disubstituted amino group.

The term “monosubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith one hydrogen and one group other than hydrogen, and includes groupsselected from —NH(R^(bb)), —NHC(═O)R^(aa), —NHCO₂R^(aa),—NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂, —NHSO₂R^(aa),—NHP(═O)(OR^(cc))₂, and —NHP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb) andR^(cc) are as defined herein, and wherein R^(bb) of the group—NH(R^(bb)) is not hydrogen.

The term “disubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith two groups other than hydrogen, and includes groups selected from—N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—NR^(bb)SO₂R^(aa), —NR^(bb)P(═O)(OR^(cc))₂, and —NR^(bb)P(═O)(NR^(bb))₂,wherein R^(aa), R^(bb), and R^(cc) are as defined herein, with theproviso that the nitrogen atom directly attached to the parent moleculeis not substituted with hydrogen.

The term “trisubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith three groups, and includes groups selected from —N(R^(bb))₃ and—N(R^(bb))₃ ⁺X⁻, wherein R^(bb) and X⁻ are as defined herein.

The term “sulfonyl” refers to a group selected from —SO₂N(R^(bb))₂,—SO₂R^(aa), and —SO₂OR^(aa), wherein R^(aa) and R^(bb) are as definedherein.

The term “sulfinyl” refers to the group —S(═O)R^(aa), wherein R^(aa) isas defined herein.

The term “acyl” refers to a group having the general formula—C(═O)R^(X1), —C(═O)OR^(X1), —C(═O)—C(═O)R^(X1), —C(═O)SR^(X1),—C(═O)N(R^(X1))₂, —C(═S)R^(X1), —C(═S)N(R^(X1))₂, and —C(═S)S(R^(X1)),—C(═NR^(X1))R^(X1), —C(═NR^(X1))OR^(X1), —C(═NR^(X1))SR^(X1), and—C(═NR^(X1))N(R^(X1))₂, wherein R^(X1) is hydrogen; halogen; substitutedor unsubstituted hydroxyl; substituted or unsubstituted thiol;substituted or unsubstituted amino; substituted or unsubstituted acyl,cyclic or acyclic, substituted or unsubstituted, branched or unbranchedaliphatic; cyclic or acyclic, substituted or unsubstituted, branched orunbranched heteroaliphatic; cyclic or acyclic, substituted orunsubstituted, branched or unbranched alkyl; cyclic or acyclic,substituted or unsubstituted, branched or unbranched alkenyl;substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, aliphaticoxy,heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy,aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy,arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- ordi-heteroaliphaticamino, mono- or di-alkylamino, mono- ordi-heteroalkylamino, mono- or di-arylamino, or mono- ordi-heteroarylamino; or two R^(X1) groups taken together form a 5- to6-membered heterocyclic ring. Exemplary acyl groups include aldehydes(—CHO), carboxylic acids (—CO₂H), ketones, acyl halides, esters, amides,imines, carbonates, carbamates, and ureas. Acyl substituents include,but are not limited to, any of the substituents described herein, thatresult in the formation of a stable moiety (e.g., aliphatic, alkyl,alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl,thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino,heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl,aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like,each of which may or may not be further substituted).

The term “carbonyl” refers a group wherein the carbon directly attachedto the parent molecule is sp² hybridized, and is substituted with anoxygen, nitrogen or sulfur atom, e.g., a group selected from ketones(—C(═O)R^(aa)), carboxylic acids (—CO₂H), aldehydes (—CHO), esters(—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)), amides (—C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), and imines(—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(cc)), —C(═NR^(bb))N(R^(bb))₂),wherein R^(aa) and R^(bb) are as defined herein.

The term “silyl” refers to the group —Si(R^(aa))₃, wherein R^(aa) is asdefined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(bb))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), p-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on an sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

The term “acyl” refers to a group having the general formula—C(═O)R^(X1), —C(═O)OR^(X1), —C(═O)—O—C(═O)R^(X1), —C(═O)SR^(X1),—C(═O)N(R^(X1))₂, —C(═S)R^(X1), —C(═S)N(R^(X1))₂, and —C(═S)S(R^(X1)),—C(═NR^(X1))R^(X1), —C(═NR^(X1))OR^(X1), —C(═NR^(X1))SR^(X1), and—C(═NR^(X1))N(R^(X1))₂, wherein R^(X1) is hydrogen; halogen; substitutedor unsubstituted hydroxyl; substituted or unsubstituted thiol;substituted or unsubstituted amino; substituted or unsubstituted acyl,cyclic or acyclic, substituted or unsubstituted, branched or unbranchedaliphatic; cyclic or acyclic, substituted or unsubstituted, branched orunbranched heteroaliphatic; cyclic or acyclic, substituted orunsubstituted, branched or unbranched alkyl; cyclic or acyclic,substituted or unsubstituted, branched or unbranched alkenyl;substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, aliphaticoxy,heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy,aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy,arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- ordi-heteroaliphaticamino, mono- or di-alkylamino, mono- ordi-heteroalkylamino, mono- or di-arylamino, or mono- ordi-heteroarylamino; or two R^(X1) groups taken together form a 5- to6-membered heterocyclic ring. Exemplary acyl groups include aldehydes(—CHO), carboxylic acids (—CO₂H), ketones, acyl halides, esters, amides,imines, carbonates, carbamates, and ureas. Acyl substituents include,but are not limited to, any of the substituents described herein, thatresult in the formation of a stable moiety (e.g., aliphatic, alkyl,alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl,thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino,heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl,aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like,each of which may or may not be further substituted).

As used herein, a “leaving group” (LG) is an art-understood termreferring to a molecular fragment that departs with a pair of electronsin heterolytic bond cleavage, wherein the molecular fragment is an anionor neutral molecule. As used herein, a leaving group can be an atom or agroup capable of being displaced by a nucleophile. See, for example,Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplaryleaving groups include, but are not limited to, halo (e.g., chloro,bromo, iodo), —OR^(aa) (when the O atom is attached to a carbonyl group,wherein R^(aa) is as defined herein), —O(C═O)R^(LG), or —O(SO)₂R^(LG)(e.g., tosyl, mesyl, besyl), wherein R^(LG) is optionally substitutedalkyl, optionally substituted aryl, or optionally substitutedheteroaryl. In some cases, the leaving group is a halogen. In someembodiments, the leaving group is I.

As used herein, use of the phrase “at least one instance” refers to 1,2, 3, 4, or more instances, but also encompasses a range, e.g., forexample, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to3, or from 3 to 4 instances, inclusive.

A “non-hydrogen group” refers to any group that is defined for aparticular variable that is not hydrogen.

The term “carbohydrate” or “saccharide” refers to an aldehydic orketonic derivative of polyhydric alcohols. Carbohydrates includecompounds with relatively small molecules (e.g., sugars) as well asmacromolecular or polymeric substances (e.g., starch, glycogen, andcellulose polysaccharides). The term “sugar” refers to monosaccharides,disaccharides, or polysaccharides. Monosaccharides are the simplestcarbohydrates in that they cannot be hydrolyzed to smallercarbohydrates. Most monosaccharides can be represented by the generalformula C_(y)H_(2y)O_(y) (e.g., C₆H₁₂O₆ (a hexose such as glucose)),wherein y is an integer equal to or greater than 3. Certain polyhydricalcohols not represented by the general formula described above may alsobe considered monosaccharides. For example, deoxyribose is of theformula C₅H₁₀O₄ and is a monosaccharide. Monosaccharides usually consistof five or six carbon atoms and are referred to as pentoses and hexoses,receptively. If the monosaccharide contains an aldehyde it is referredto as an aldose; and if it contains a ketone, it is referred to as aketose. Monosaccharides may also consist of three, four, or seven carbonatoms in an aldose or ketose form and are referred to as trioses,tetroses, and heptoses, respectively. Glyceraldehyde anddihydroxyacetone are considered to be aldotriose and ketotriose sugars,respectively. Examples of aldotetrose sugars include erythrose andthreose; and ketotetrose sugars include erythrulose. Aldopentose sugarsinclude ribose, arabinose, xylose, and lyxose; and ketopentose sugarsinclude ribulose, arabulose, xylulose, and lyxulose. Examples ofaldohexose sugars include glucose (for example, dextrose), mannose,galactose, allose, altrose, talose, gulose, idose, desosamine, andmycaminose; and ketohexose sugars include fructose, psicose, sorbose,and tagatose. Ketoheptose sugars include sedoheptulose. Each carbon atomof a monosaccharide bearing a hydroxyl group (—OH), with the exceptionof the first and last carbons, is asymmetric, making the carbon atom astereocenter with two possible configurations (R or S). Because of thisasymmetry, a number of isomers may exist for any given monosaccharideformula. The aldohexose D-glucose, for example, has the formula C₆H₁₂O₆,of which all but two of its six carbons atoms are stereogenic, makingD-glucose one of the 16 (i.e., 24) possible stereoisomers. Theassignment of D or L is made according to the orientation of theasymmetric carbon furthest from the carbonyl group: in a standardFischer projection if the hydroxyl group is on the right the molecule isa D sugar, otherwise it is an L sugar. The aldehyde or ketone group of astraight-chain monosaccharide will react reversibly with a hydroxylgroup on a different carbon atom to form a hemiacetal or hemiketal,forming a heterocyclic ring with an oxygen bridge between two carbonatoms. Rings with five and six atoms are called furanose and pyranoseforms, respectively, and exist in equilibrium with the straight-chainform. During the conversion from the straight-chain form to the cyclicform, the carbon atom containing the carbonyl oxygen, called theanomeric carbon, becomes a stereogenic center with two possibleconfigurations: the oxygen atom may take a position either above orbelow the plane of the ring. The resulting possible pair ofstereoisomers is called anomers. In an a anomer, the —OH substituent onthe anomeric carbon rests on the opposite side (trans) of the ring fromthe —CH₂OH side branch. The alternative form, in which the —CH₂OHsubstituent and the anomeric hydroxyl are on the same side (cis) of theplane of the ring, is called a β anomer. A carbohydrate including two ormore joined monosaccharide units is called a disaccharide orpolysaccharide (e.g., a trisaccharide), respectively. The two or moremonosaccharide units bound together by a covalent bond known as aglycosidic linkage formed via a dehydration reaction, resulting in theloss of a hydrogen atom from one monosaccharide and a hydroxyl groupfrom another. Exemplary disaccharides include sucrose, lactulose,lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose,laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, orrutinose. Exemplary trisaccharides include, but are not limited to,isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose,raffinose, and kestose. The term carbohydrate also includes othernatural or synthetic stereoisomers of the carbohydrates describedherein.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

As used herein, the term “salt” refers to any and all salts, andencompasses pharmaceutically acceptable salts.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acids,such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids, such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate. A “counterion” or“anionic counterion” is a negatively charged group associated with apositively charged group in order to maintain electronic neutrality. Ananionic counterion may be monovalent (i.e., including one formalnegative charge). An anionic counterion may also be multivalent (i.e.,including more than one formal negative charge), such as divalent ortrivalent. Exemplary counterions include halide ions (e.g., F⁻, Cl⁻,Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions (e.g.,methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF⁻,B[3,5-(CF₃)₂C₆H₃]₄]⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, and a carborane anion(e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻).

The term “solvate” refers to forms of the compound, or a salt thereof,that are associated with a solvent, usually by a solvolysis reaction.This physical association may include hydrogen bonding. Conventionalsolvents include water, methanol, ethanol, acetic acid, DMSO, THF,diethyl ether, and the like. The compounds described herein may beprepared, e.g., in crystalline form, and may be solvated. Suitablesolvates include pharmaceutically acceptable solvates and furtherinclude both stoichiometric solvates and non-stoichiometric solvates. Incertain instances, the solvate will be capable of isolation, forexample, when one or more solvent molecules are incorporated in thecrystal lattice of a crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Representative solvates includehydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R·x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R·0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R·2 H₂O) and hexahydrates (R·6 H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertable compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorph” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof). All polymorphs have the sameelemental composition. Different crystalline forms usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Various polymorphs of a compound can beprepared by crystallization under different conditions.

The term “isotopically labeled derivative” refers to a compound whereinone or more atoms in the compound has been replaced with an isotope ofthe same element. For the given element or position in the molecule theisotope will be enriched, or present in a higher percentage of all atomsof the element or of all atoms at the position in the molecule in asample, relative to an unlabeled sample. In certain embodiments, theenriched isotope will be a radioactive isotope (e.g., a radionuclide).

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Synthesis of D-Desosamine (1)

The optimized 4-step sequence to D-desosamine (1) is shown in Scheme E1,and begins with the transformation of methyl vinyl ketone to4-nitro-2-butanone (3). Miyakoshi et al. have shown that conjugativeaddition of sodium nitrite to methyl vinyl ketone in a mixed solvent ofacetic acid and THF provides 4-nitro-2-butanone in 82% yield. See, e.g.,Miyakoshi et al., Chem. Lett.) (1981) 10:1677-1678; Miyakoshi et al.,Nippon Kagaku Kaishi (1984) 1984:458-462. When we employed this methodto prepare 3 we did successfully obtain the desired product, but it wascontaminated with 4-acetoxy-2-butanone as a by-product (˜4:1 ratio,respectively) and the mixture proved challenging to separate. A way toobviate this problem is substitution of pyridinium trifluoroacetate foracetic acid. Thus, addition of trifluoroacetic acid (86.0 mL, 1.30equiv.) to a solution of pyridine (91.0 mL, 1.30 equiv.) in THF (1.0 L)at 0° C. over 10 minutes led to a suspension of pyridiniumtrifluoroacetate. Admixture of methyl vinyl ketone (60.0 g, 1 equiv.)with sodium nitrite (70.9 g, 1.20 equiv.) and this suspension at 23° C.for 16 hours followed by an extractive isolation procedure (ethylacetate) afforded 4-nitro-2-butanone in a high state of purity in 50%yield (50.4 g). Yields as high as 79% have also been obtained by usingself-prepared pyridinium trifluoroacetate and careful workup to accountfor the product being low boiling and highly water soluble. While it hasbeen reported that 3 can be purified by distillation, we do notrecommend this, as distillation may lead to decomposition (browning)with bumping, likely due to retro-Michael addition to form nitrous acidand methyl vinyl ketone. Because 3 is formed in a high state purity bythe modified method, no further purification is necessary.

Slow addition of the “crude” ketone 3 to a mixture of theCorey-Bakshi-Shibata oxazaborolidine catalyst 4 (20 mol %) andborane-tetrahydrofuran complex (0.8 equiv.) afforded the secondaryalcohol 5 in 65% yield (33.3 g) and 87% ee (Mosher ester analysis, See,e.g., Dale et al., J. Am. Chem. Soc. (1973) 95:512-519; Hoye et al.,Nat. Protocols (2007) 2:2451:2458) after purification by extractiveisolation (ethyl acetate) and distillation (1.2 mmHg, 80° C.). See,e.g., Corey et al., J. Am. Chem. Soc. (1987) 109:5551-5553; Angew. Chem.Int. Ed. (1998) 37:1986-2012. The use of a substoichiometric amount ofborane and slow addition of the ketone led to reproducibly highenantioselectivities (86-89% ee). Yields as high as 70% have also beenobtained. The aminoalcohol ligand (S)-1,1-diphenylprolinol was readilyrecovered (in 80% yield) from the reaction mixture by extraction withaqueous acid, neutralization, extraction with dichloromethane andrecrystallization, and could be used to regenerate the catalyst 4 in onestep.

In the cyclization step, a biphasic mixture of nitro alcohol 5 (33.3 g,1 equiv., ˜2.6 M in 3:1 dichloromethane:water), 40% aqueous glyoxal(42.6 mL, 1.05 equiv.) and sodium carbonate (1.5 g, 5 mol %) was stirredat 4° C. for 16 hours, leading to direct precipitation of the nitrosugar 6 from the reaction mixture. After filtration of the reactionsolution through a sintered glass filter funnel, the product wasobtained in pure form in 41% yield as a white powder (20.1 g). ChiralHPLC analysis established that the product was >99% ee, which issubstantially higher than the ee of the starting nitro alcohol 5.Although further purification of 6 is unnecessary; if desired, it can berecrystallized from hot n-butanol (87% recovery). X-ray crystallographicanalysis of crystals obtained from n-butanol confirmed thestereochemistry of the nitro sugar was homologous with D-desosamine. ¹HNMR analysis of a CD₃OD solution of 6 showed a mixture of α and βanomers, ˜15:1.

Completion of the synthesis was achieved wherein sequential nitroreduction and reductive amination were conducted in a single step. Asuspension of 6 (15.0 g, 1 equiv.) and palladium hydroxide on carbon (20wt. % loading, 6.0 g) in 9:1 methanol:acetic acid (420 mL) was stirredunder H₂ (1 atm) at 23° C. Aqueous formaldehyde (37 wt. %, 15.8 mL, 2.50equiv.) was added when TLC analysis indicated full consumption ofstarting material (typically in 8 hours), and the mixture was stirredfor additional 12 hours. Filtration of the reaction solution throughCelite, concentration of the filtrate and neutralization of the acetatesalt with Amberlyst A26 resin afforded D-desosamine (1) as a colorlessliquid in 94% yield. This process is amenable to large-scale synthesis,and we have prepared 20-g batches of D-desosamine in about 4 days.

4-nitrobutane-2-one (3)

Trifluoroacetic acid (86.0 mL, 1.11 mol, 1.30 equiv) was added to astirred mixture of pyridine (91.0 mL, 1.11 mol, 1.30 equiv) and THF(1000 mL) at 0° C. After 10 minutes, sodium nitrite (70.9 g, 1.03 mol,1.20 equiv) and methyl vinyl ketone (60.0 g, 856 mmol, 1 equiv) wereadded. The reaction mixture was warmed to 23° C. and stirred for 18hours. Water (700 mL) and ether (500 mL) were added and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (7×300mL). The combined organic layers were concentrated to ˜500 mL, andwashed with 1 N HCl (2×400 mL). The combined aqueous layers wereextracted with ethyl acetate (5×300 mL). The combined organic layer waswashed with half saturated aqueous sodium bicarbonate solution (300 mL).The aqueous layer was extracted with ethyl acetate (3×300 mL). Thecombined organic layers were washed with brine (300 mL), dried overmagnesium sulfate, and concentrated to afford 4-nitrobutan-2-one (50.4g, 50%). ¹H NMR (500 MHz, CDCl₃) δ 4.63 (td, J=6.2, 2.4 Hz, 2H), 3.09(t, J=6.0 Hz, 2H), 2.27 (d, J=2.3 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ203.5, 68.8, 38.9, 29.7. FTIR (neat), cm⁻¹: 2924 (m), 1720 (s), 1554(s), 1400 (s), 1375 (s), 1127 (s). HRMS (ESI): Calcd for (C₄H₇NO₃+Na)⁺:140.0318; Found: 140.0319.

(R)-4-nitrobutane-2-ol (5)

To a flame-dried flask was charged borane-tetrahydrofuran complex (1.0 Min THF, 344 mL, 344 mmol, 0.800 equiv) and THF (1.0 L). The solution wascooled to −10° C. (ice-salt bath) and(S)-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole(86 mL, 86 mmol, 0.20 equiv) was added as a 1.0 M solution in toluene. Asolution of 4-nitrobutan-2-one (50.4 g, 430 mmol) in THF (120 mL) wasadded dropwise over 60 minutes. The internal temperature was maintainedat −10° C. over the course of addition. The reaction mixture was stirredat −10° C. After 30 minutes, methanol (150 mL) was added, and themixture was vigorously stirred for 10 minutes. 1 N HCl (600 mL) wasadded and the mixture was stirred for additional 10 minutes. The mixturewas extracted with ether (500 mL) followed by ethyl acetate (7×500 mL).The combined organic layers were dried over magnesium sulfate andconcentrated. After concentration, the crude mixture was diluted withether (500 mL) and filtered through a pad of Celite. The solution waswashed with 1 N HCl (2×200 mL) and brine (200 mL). The aqueous acidlayers were combined for the recovery of (S)-1,1-diphenylprolinol (videinfra). The organic layer was dried over magnesium sulfate andconcentrated. The crude product was purified by distillation (1.2 mmHg,80° C.) to give the title compound as pale yellow oil (33.3 g, 65%). ¹HNMR (500 MHz, CDCl₃) δ 4.69-4.43 (m, 2H), 4.00-3.88 (m, 1H), 2.28-2.18(m, 1H), 2.08-2.00 (m, 1H), 1.65 (br, 1H), 1.29 (d, J=6.2 Hz, 3H). ¹³CNMR (126 MHz, CDCl₃) δ 72.5, 64.9, 35.8, 23.7. FTIR (neat), cm⁻¹: 3389(br), 2972 (m), 1548 (s), 1379 (s), 1130 (s), 1103 (s). HRMS (ESI):Calcd for (C₄H₉NO₃+Na)⁺: 142.0475; Found: 142.0482.

Determination of Enantiomeric Excess:

Crude 5 (10 mg, 0.088 mmol, 1 equiv) was dissolved in dichloromethane(0.2 mL). Pyridine (14.0 μL, 0.168 mmol, 2.00 equiv) and (R)-(−)-MTPAacid chloride (42.5 mg, 0.168 mmol, 2.00 equiv) were added at 23° C. Thesolution was stirred for 1 hour and concentrated. ¹H NMR was taken ofthe residue. Enantiomeric excess was calculated from integrations ofmethyl doublets at 1.42 ppm (desired) and 1.35 ppm (undesired). The eeof this sample was found to be 87%.

Recovery of (S)-1,1-diphenylprolinol

The combined acid layers were treated with 6 N NaOH until the pH reaches13. The mixture was extracted with dichloromethane (3×500 mL). Thecombined organic layers were dried over magnesium sulfate andconcentrated to give (S)-1,1-diphenylprolinol as a white solid. Thissolid was recrystallized from hot heptane (3 mL/g) to give the recoveredamino alcohol as colorless crystals.

4-nitro-4,5,6-trideoxy-α-D-glucose (6)

To the solution of sodium carbonate (1.48 g, 14.0 mmol, 0.0500 equiv) inwater (28.0 mL) were added sequentially glyoxal (40 wt. % in water, 42.6mL, 294 mmol, 1.05 equiv), (R)-4-nitrobutan-2-ol (5) (33.3 g, 280 mmol,1 equiv, 87% ee) and dichloromethane (80 mL). The biphasic mixture wasvigorously stirred at 4° C. for 16 hours. Ether (100 mL) was added tothe reaction mixture. The reaction mixture was filtered through asintered glass funnel. The filter cake was washed with ether (2×50 mL)and dried under vacuum to give the title compound as a white powder(20.1 g, 41%). ¹H NMR (15:1 α:β anomeric mixture, 500 MHz, CD₃OD)α-anomer: δ 5.15 (d, J=3.5 Hz, 1H), 4.93-4.88 (m, 1H), 4.20 (dqd,J=12.5, 6.2, 2.2 Hz, 1H), 3.97 (dd, J=10.3, 3.6 Hz, 1H), 2.26 (ddd,J=12.4, 4.5, 2.3 Hz, 1H), 1.83 (app q, J=12.2 Hz, 1H), 1.20 (d, J=6.3Hz, 3H). β-anomer: δ 4.65 (ddd, J=12.3, 10.0, 4.8 Hz, 1H), 4.49 (d,J=7.7 Hz, 1H), 3.77-3.70 (m, 1H), 3.68 (dd, J=10.0, 7.7 Hz, 1H),2.30-2.20 (m, 1H), 1.83 (app q, J=12.4 Hz, 1H), 1.25 (d, J=6.2 Hz, 3H).¹³C NMR (15:1 α:β anomeric mixture, 126 MHz, CD₃OD) α-anomer: δ 93.8,86.3, 71.5, 63.3, 38.8, 20.9. β-anomer δ 97.9, 88.8, 73.7, 69.3, 39.0,21.0. FTIR (neat), cm⁻¹: 3323 (br), 2933 (m), 2470 (s), 1720 (s), 1552(s), 1384 (s), 1267 (s), 1155 (s), 1095 (s), 1039 (s). HRMS (ESI): Calcdfor (C₆H₁₁NO₅+Na)⁺: 200.0529; Found: 200.0517.

The product is pure by ¹H NMR analysis. But if desired, it could berecrystallized from hot n-butanol (5.5 mL/g) to give the product ascolorless crystals (15.0 g, 75% recovery).

Enantiomeric excess was determined by chiral HPLC (Chiralcel OC—HColumn, Daicel Corp., Eluent: 10% iPrOH-Hexane, Detector Wavelength=210nm). t_(R) (major)=18.4 minutes, t_(R) (minor)=22.8 minutes. Samplesbefore and after recrystallization were both found to be have >99% ee.

D-Desosamine (1)

4-nitro-4,5,6-trideoxy-α-D-glucose (6) (15.0 g, 85.0 mmol) was dissolvedin 9:1 methanol:acetic acid (420 mL) in a 1-L flask. 20 wt. % Palladiumhydroxide on carbon (5.95 g, 8.47 mmol) was added. The flask wasevacuated and refilled with argon (3 times). The evacuation-refill cyclewas repeated with hydrogen gas (2 times). The suspension was stirred at23° C. under hydrogen atmosphere (balloon pressure) and the reactionprogress was monitored by TLC (100% ether). After full consumption ofstarting material (typically in 8 hours), aqueous formaldehyde (37 wt. %in water, 15.8 mL, 212 mmol) was added. The mixture was kept stirred at23° C. under hydrogen atmosphere for 15 hours. The mixture was filteredthrough a thin pad of Celite (˜30 g), rinsing with methanol (˜100 mL).The filtrate was concentrated and the residue was dissolved in methanol(300 mL). To the solution was added Amberlyst A26 resin (OH form, 300g). The slurry was stirred at 23° C. for 1 hour, and filtered through asintered glass funnel. The resin was rinsed with 300 mL methanol. Thefiltrate was concentrated to give D-desosamine (13.9 g, 94%, α:β˜1:1.6).¹H NMR (1:1.6 α:β anomeric mixture, 500 MHz, CD₃OD) α-anomer: δ 5.09 (d,J=3.6 Hz, 1H), 4.12 (dqd, J=12.6, 6.1, 2.0 Hz, 1H), 3.53 (dd, J=10.6,3.6 Hz, 1H), 2.96 (ddd, J=12.2, 10.7, 3.9 Hz, 1H), 2.34 (s, 6H),1.81-1.72 (m, 1H), 1.30-1.22 (m, 1H), 1.14 (d, J=6.3 Hz, 3H). β-anomer:δ 4.41 (d, J=7.4 Hz, 1H), 3.61 (dqd, J=12.4, 6.2, 1.9 Hz, 1H), 3.20 (dd,J=10.2, 7.4 Hz, 1H), 2.61 (ddd, J=12.3, 10.3, 4.2 Hz, 1H), 2.33 (s, 6H),1.76 (ddt, J=12.8, 4.2, 2.1 Hz, 1H), 1.28-1.19 (m, 1H), 1.22 (d, J=6.2Hz, 3H). ¹³C NMR (1:1.6 α:β anomeric mixture, peaks are reportedcollectively, 126 MHz, CD₃OD) δ 99.3, 94.4, 72.9, 70.7, 70.5, 65.6,65.2, 60.8, 40.8, 40.7, 33.0, 32.0, 21.5. FTIR (neat), cm⁻¹: 3399 (br),2937 (m), 2486 (s), 2069 (s), 1556 (m), 1384 (m), 1120 (s), 1082 (s),1042 (s), 980 (s). HRMS (ESI): Calcd for (C₈H₁₇NO₃+H)⁻: 176.1281; Found:176.1276.

Thioglycosidation of D-Desosamine

As shown in Scheme E2, D-Desosamine (1) can be transformed into theprotected thioglycoside 8, an anomerically activated form of desosamineoptimized for glycosidic coupling reactions by Woodward and coworkers intheir landmark synthesis of erythromycin A. See, e.g., Woodward et al.,J. Am. Chem. Soc. (1981) 103:3215-3217. The original Woodward procedureinvolved a Mitsunobu reaction (n-Bu3P, DEAD, 2-mercaptopyrimidine) foranomeric activation followed by protection of the free 2-hydroxyl group(ClCO2CH3/NaHCO3, 63% over 2 steps). Herein we describe a more practicalas well as economical two-step transformation. Thus, treatment ofD-desosamine (9.33 g, 1 equiv.) with methylchloroformate (12.4 mL, 3.00equiv.) and diisopropylethylamine (27.9 mL, 3.00 equiv.) indichloromethane (106 mL) at 0° C. for 1 hour led to formation ofdimethyl biscarbonate 7 (12.0 g, 78%, α:β ˜1:1.5). Addition oftrimethylsilyl triflate (13.7 mL, 2.00 equiv.) to a mixture of 7 (11.0g, 1 equiv.), 2-mercaptopyrimidine (4.24 g, 1.00 equiv.), 2,6-lutidine(8.8 mL, 2.00 equiv.) in dichloromethane (76 mL) followed by stirringfor 19 hours at 4° C. afforded thioglycoside 8 (69%, α:β ˜1:10) afterpurification by column chromatography.

D-desosamine-1,2-dimethyl biscarbonate (7)

D-desosamine (9.33 g, 53.2 mmol) was dissolved in dichloromethane (106mL) and cooled to 0° C. Hunig's Base (27.9 mL, 160 mmol) and methylchloroformate (12.4 mL, 160 mmol) were added sequentially. After 1 hour,100 mL saturated sodium bicarbonate solution was added to the reactionmixture. The resulting biphasic mixture was stirred for 5 minutes, andextracted with dichloromethane (3×100 mL). The combined organic layerswere dried over sodium sulfate and concentrated. The residue wasdissolved in ether (250 mL) and 1 N HCl (100 mL). The layers wereseparated and the ether layer was extracted with 1N HCl (2×50 mL). Thecombined aqueous layers were neutralized with solid sodium bicarbonateuntil pH=8. The milky aqueous mixture was extracted with ether (3×200mL). The combined organic layers were dried over magnesium sulfate andconcentrated to provide the title compound as a colorless oil (12.0 g,78%, α:β˜1:1.5). ¹H NMR (1:1.5 α:β anomeric mixture, 500 MHz, CDCl₃)α-anomer: δ 6.17 (d, J=3.6 Hz, 1H), 4.85 (dd, J=11.1, 3.6 Hz, 1H),4.14-4.05 (m, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.20 (app td, J=11.8, 4.0Hz, 1H), 2.32 (s, 6H), 1.87 (ddd, J=13.2, 3.9, 2.3 Hz, 1H), 1.45 (app q,J=10.8 Hz, 1H), 1.23 (d, J=6.2 Hz, 3H). β-anomer: δ 5.46 (d, J=7.9 Hz,1H), 4.73 (dd, J=10.5, 7.9 Hz, 1H), 3.78-3.70 (m, 1H), 2.84 (ddd,J=12.3, 10.6, 4.3 Hz, 1H), 2.31 (s, 6H), 1.82 (ddd, J=13.3, 4.2, 1.9 Hz,1H), 1.42 (app q, J=11.5 Hz, 1H), 1.30 (d, J=6.1 Hz, 3H). ¹³C NMR (1:1.5α:β anomeric mixture, peaks are reported collectively, 126 MHz, CDCl₃) δ155.0, 154.9, 154.4, 154.3, 96.9, 94.4, 77.2, 73.3, 72.5, 70.5, 67.3,63.2, 57.6, 55.0, 55.0, 54.9, 40.6, 40.4, 31.3, 29.9, 21.0, 20.9. FTIR(neat), cm⁻¹: 2958 (m), 1751 (s), 1442 (s), 1274 (s), 1250 (s), 1084(s), 979 (s). HRMS (ESI): Calcd for (C₁₂H₂₁NO₇+H)⁺: 292.1391; Found:292.1395.

Thioglycoside 8

2-mercaptopyrimidine (4.24 g, 37.8 mmol) and 2,6-lutidine (8.80 mL, 76mmol) were added to a solution of D-desosamine-1,2-dimethyl biscarbonate(11.0 g, 37.8 mmol) in dichloromethane (76 mL). The mixture was cooledto 0° C. and trimethylsilyl trifluoromethanesulfonate (13.7 mL, 76 mmol)was added dropwise. After addition, the flask was transferred to a 4° C.cold room and stirred for 19 hours. Saturated sodium bicarbonatesolution (200 mL) was added, and the biphasic mixture was vigorouslystirred for 30 minutes (gas evolution). The layers were separated andthe aqueous layer was extracted with dichloromethane (2×100 mL). Thecombined organic layers were dried over sodium sulfate and concentrated.The residue was purified by column chromatography over silica gel (30%acetone-hexanes) to afford the title compound as a yellow foam (8.5 g,69%, α:β ˜1:10). ¹H NMR (1:10 α:β anomeric mixture, 500 MHz, CDCl₃)α-anomer: δ 8.53 (d, J=4.9 Hz, 3H), 6.98 (t, J=4.8 Hz, 1H), 6.76 (d,J=5.3 Hz, 1H), 5.07 (dd, J=11.1, 5.3 Hz, 1H), 3.73 (s, 3H), 3.04-2.96(m, 1H), 2.33 (s, 6H), 1.86 (ddd, J=13.2, 4.3, 1.8 Hz, 1H), 1.49 (apptd, J=12.6, 11.2 Hz, 1H), 1.21 (d, J=6.1 Hz, 3H). β-anomer: δ 8.51 (d,J=4.8 Hz, 2H), 6.98 (t, J=4.8 Hz, 1H), 5.69 (d, J=10.1 Hz, 1H), 4.85(app t, J=10.1 Hz, 1H), 3.77 (s, 3H), 2.92 (ddd, J=12.4, 10.0, 4.3 Hz,1H), 2.32 (s, 6H), 1.86 (ddd, J=13.2, 4.3, 1.8 Hz, 1H), 1.49 (app td,J=12.6, 11.2 Hz, 1H), 1.27 (d, J=6.2 Hz, 3H). ¹³C NMR (1:10 α:β anomericmixture, β-anomer is reported, 126 MHz, CDCl₃) δ 170.2, 157.3, 117.1,83.1, 73.7, 72.3, 64.8, 55.0, 40.7, 31.1, 21.3. FTIR (neat), cm⁻¹: 2974(m), 1749 (s), 1550 (s), 1381 (s), 1274 (s), 1055 (s), 738 (s). HRMS(ESI): Calcd for (C₁₄H₂₁N₃O₄S+H)⁺: 328.1326; Found: 328.1333.

Synthesis of Desosamine Analogs

N-protected derivatives of desosamine can be readily accessed (SchemeE3) from the acetate salt of primary amine 9, which in turn was preparedfrom catalytic hydrogenation of nitro sugar 6 following the protocoldescribed for desosamine in the absence of formaldehyde. Heating amixture of 9 (100 mg, 1 equiv.), potassium carbonate (267 mg, 4.00equiv.) and benzyl bromide (115 μL, 2.00 equiv.) at 80° C. for 1 hourled to formation of N,N-dibenzyl derivative 10 (136 mg, 81%). Treatmentof 9 (415 mg, 1 equiv.) with di-tert-butyl dicarbonate (446 μL, 1.20equiv.) and sodium bicarbonate (538 mg, 4.00 equiv.) affordedN-tert-butoxycarbonyl derivative 11 (278 mg, 70%).

4-amino-4,5,6-trideoxy-D-glucose hydroacetate (9)

4-nitro-4,5,6-trideoxy-α-D-glucose (1.72 g, 9.71 mmol) was dissolved in9:1 MeOH/AcOH (48 mL). 20 wt. % Palladium hydroxide on carbon (682 mg,8.47 mmol) was added. The flask was evacuated and refilled with argon (3times). The evacuation-refill cycle was repeated with hydrogen gas (2times). The suspension was stirred at 23° C. under hydrogen atmosphere(balloon pressure) and the reaction progress was monitored by TLC (100%ether). After 6 hours, The mixture was filtered through a thin pad ofcelite and washed with methanol (˜50 mL) The filtrate was concentratedto afford the title compound as an orange oil (2.01 g, 100%).

4-dibenzylamino-4,5,6-trideoxy-D-glucose (10)

4-amino-4,5,6-trideoxy-D-glucose hydroacetate (100 mg, 0.483 mmol) wasdissolved in 2:1 ethanol/water (1.0 mL). Potassium carbonate (267 mg,1.93 mmol) and benzyl bromide (115 μL, 0.965 mmol) were addedsequentially. The biphasic mixture was heated to 80° C. for 1 hour. Thereaction mixture was cooled to 23° C., diluted with water (2 mL), andextracted with ether (3×5 mL). The combined ether layers were washedwith brine and dried over magnesium sulfate. The solution was filteredand concentrated. The residue was dissolved in ether (10 mL) and thesolution was extracted with 1 N HCl (3×1 mL). The ether layer wasdiscarded, and the combined acid layers were neutralized with solidsodium bicarbonate to pH=8. The mixture was extracted withdichloromethane (3×5 mL). The combined organic layer were dried oversodium sulfate and concentrated to provide the title compound as a paleyellow oil (136 mg, 81%, α:β ˜1:2.0). ¹H NMR (500 MHz, CDCl₃) α-anomer:δ 5.33 (d, J=3.5 Hz, 1H), 4.16-4.03 (m, 1H), 3.87 (d, J=13.3 Hz, 2H),3.66 (dd, J=10.5, 3.6 Hz, 1H), 3.45 (d, J=13.4 Hz, 2H), 3.09 (ddd,J=12.2, 10.7, 3.6 Hz, 1H), 1.96-1.80 (m, 1H), 1.50-1.36 (m, 1H), 1.24(d, J=6.2 Hz, 3H). β-anomer: δ 4.42 (d, J=7.2 Hz, 2H), 3.89 (d, J=13.3Hz, 2H), 3.58-3.50 (m, 1H), 3.41 (d, J=13.5 Hz, 2H), 3.40 (dd, J=10.1,7.2 Hz, 1H), 2.68 (ddd, J=12.4, 10.3, 3.9 Hz, 1H), 1.96-1.80 (m, 1H),1.50-1.36 (m, 1H), 1.31 (d, J=6.2 Hz, 3H). ¹³C NMR (1:2.0 α:β anomericmixture, peaks are reported collectively, 126 MHz, CDCl₃) δ 140.0,139.1, 139.0, 128.8, 128.7, 128.5, 128.5, 128.3, 128.1, 127.3, 127.2,126.9, 97.8, 92.4, 71.2, 69.8, 68.1, 65.3, 59.6, 55.4, 53.7, 53.6, 53.0,30.8, 30.3, 21.3. FTIR (neat), cm⁻¹: 3419 (br), 2920 (m), 1454 (s), 1045(s), 738 (s), 698 (s). HRMS (ESI): Calcd for (C₂₀H₂₅NO₃+H)⁺: 328.1914;Found: 328.1907.

The use of different β-nitroalcohols in place of (R)-4-nitrobutan-2-ol(5) provides a route to analogs of desosamine and mycanimose. An exampleis provided in Scheme E4. (S)-4-nitrobutane-1,2-diol (12) was preparedin 4 steps from (R)-glyceraldehyde acetonide (8), following a proceduredescribed in Zindel et al. (J. Org. Chem. (1995) 60:2968-2973). Diol 12underwent coupling with 40% aqueous glyoxal to give 13 in 38% yield.Although in this case precipitates did not appear in the reactionmixture, cyclization product 13 was obtained as white, needle-shapedcrystals when the crude product was treated with hot n-butanol (0.6mL/mmol) and cooled to 23° C. The nitro sugar 13 can be converted to adesosamine analog according to methods described in Scheme E1.

The synthesis of a 4-hydroxy nitro sugar is described in Scheme E5.Methyl (R)-2-hydroxypropanoate (14) was treated withtert-butyldimethylsilyl chloride and imidazole to afford the silylprotected alcohol 15 (98% yield), which was then reduced to aldehyde 16in 82% yield. An asymmetric copper catalyzed Henry reaction to couple 16and nitromethane employed the chiral bis(oxazaline) derivative 20, andformed the protected nitro diol 17 in 99% yield as a single isomer.Deprotection to give (2S,3R)-1-nitrobutane-2,3-diol (18) in 92% yieldwas accomplished by treatment with pyridinium hydrofluoride. Cyclizationof diol 18 with glyoxal yields the 4-hydroxy nitro sugar (19) as ananomeric mixture. Initial precipitation gave only the α-anomer in 29%yield. Treatment of the mother liquor with HCl-dioxane promotesepimerization of the less crystalline β-anomer providing a second cropof the α-anomer and bringing the overall yield to 41%. Nitro sugar 19can be converted to D-mycaminose via the reduction and methylation stepdescribed in Scheme E1.

Scheme E6 shows a route to 4,6-dihydroxy sugars. Treatment of(R)-glyceraldehyde acetonide (8) with nitromethane and base yields theHenry reaction product 21 in 83% yield. The desired isomer formed inexcess (4:1), and the diastereomers could be resolved byrecrystallization. Acid hydrolysis of the acetal afforded nitro triol 22in 98% yield. The cyclization of 22 with glyoxal proceeded in 42% yield,following treatment of the mother liquor with HCl-dioxane to enhancecrystallization. Nitro sugar 23 can be converted to a desosamine analogaccording to methods described in Scheme E1.

Synthesis of 6-azido-D-desosamine Derivatives

6-azido D-desosamine derivatives can be accessed as described in SchemeE7. The synthesis of methyl2-O-methoxycarbonyl-3,4-dideoxy-3-dimethylamino-β-D-xylo-hexopyranoside(31) was adapted from procedures described by Roy and co-workers. See,e.g., Giguere et al., J. Org. Chem. (2011) 76:9687-9698. Methoxycarbonylchloride was used in place of acetic anhydride in the step of protectingthe C2 hydroxyl position. From intermediate 31 a Mitsunobu reaction withdiphenylphosphoryl azide (DPPA) yields the protected 6-azidoD-desosamine derivative 32 in 81% yield. Deprotection of both hydroxylgroups would provide 6-azido D-desosamine.

32 was converted to the protected thioglycoside in two additional steps.Treatment with acetic anhydride quantitatively converts the anomericmethoxy position to acetoxy. The acetoxy group of 33 is a suitableleaving group for thioglycosidation, which was carried out withmercaptopyrimidine, trimethylsilyl triflate and 2,6-lutidine to yieldthioglycoside 34 in 68% yield.

Preparation of Nitro Sugars Bearing an Axial Substituent at 4-Position

Methods described herein are also applicable to the preparation ofsugars bearing axial groups at the 4-position of the sugars. Forexample, a single 1-g-scale reaction, coupling of(2S,3S)-4-nitrobutane-1,2,3-triol and glyoxal afforded the crystallinenitrosugar shown in Scheme E8 27% yield. Examination of its NMR spectrumindicated that this nitrosugar differs from compound 23 in that the4-hydroxy group adopts an axial configuration. In addition, when the3-hydroxy group was protected as a benzhydryl ether as shown in SchemeE8, the cyclization reaction afforded the corresponding protected nitrosugar in 58% yield after purification by column chromatography.

(S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol (S4) and(R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol (S5)

A 300-mL round-bottom flask was charged with a magnetic stir bar,(R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (29.5 g, 227 mmol, 1equiv) and THF (113 mL). The mixture was cooled to 0° C., andnitromethane (36.7 mL, 680 mmol, 3.00 equiv) and solid potassiumcarbonate (40.7 g, 295 mmol, 1.30 equiv) were added. The reactionmixture was stirred at 23° C. for 18 h. Water (100 mL) was added and themixture was extracted with ether (2×100 mL). The combined organic layerswere washed with brine (200 mL). The washed solution was dried overmagnesium sulfate, and the dried solution was concentrated. The residuewas purified by column chromatography over silica gel (30% ethylacetate-hexanes) to afford separately(S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol (S4) (32.2g, 74%) and (R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol(S5) (7.32 g, 17%).

(S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol (S4)

TLC (30% ethyl acetate-hexanes): R_(f)=0.20 (phosphomolybdic acid). ¹HNMR (500 MHz, CDCl₃) δ 4.72 (dd, J=13.2, 2.6 Hz, 1H), 4.47 (dd, J=13.2,8.8 Hz, 1H), 4.27-4.21 (m, 1H), 4.18-4.14 (m, 1H), 4.06-3.99 (m, 2H),2.78 (dd, J=5.4 Hz, 1H), 1.45 (s, 3H), 1.36 (s, 3H). ¹³C NMR (126 MHz,CD₃OD) δ 110.3, 78.0, 75.4, 70.2, 66.8, 26.7, 24.9. FTIR (neat), cm⁻¹:3437 (br), 2990 (m), 2938 (m), 2897 (m), 1555 (s), 1375 (s), 1215 (s),1153 (s), 1063 (s), 843 (s). HRMS (ESI): Calcd for (C₇H₁₃NO₅+Na)⁺:214.0686, Found: 214.0686.

(R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol (S5)

TLC (30% ethyl acetate-hexanes): R_(f)=0.15 (phosphomolybdic acid). ¹HNMR (500 MHz, CDCl₃) δ 4.55 (dd, J=13.2, 8.8 Hz, 1H), 4.51 (dd, J=13.2,3.9 Hz, 1H), 4.41-4.35 (m, 1H), 4.21 (ddd, J=6.8, 5.8, 2.9 Hz, 1H), 4.12(dd, J=8.8, 6.8 Hz, 1H), 4.00 (dd, J=8.8, 5.8 Hz, 1H), 2.55 (d, J=7.8Hz, 1H), 1.49 (s, 3H), 1.38 (s, 3H). ¹³C NMR (126 MHz, CD₃OD) δ 110.2,78.3, 75.2, 68.4, 65.4, 26.2, 24.7. FTIR (neat), cm⁻¹: 3441 (br), 2990(m), 2938 (m), 2897 (m), 1553 (s), 1375 (s), 1211 (s), 1154 (s), 1138(s), 1063 (s), 845 (s). HRMS (ESI): Calcd for (C₇H₁₃NO₅+Na)⁺: 214.0686,Found: 214.0691.

(2R,3R)-4-nitrobutane-1,2,3-triol (S6)

A 300-mL round-bottom flask was charged with a magnetic stir bar,(R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol S5 (4.16 g,21.8 mmol, 1 equiv), acetic acid (54.4 mL) and water (18.1 mL). Thereaction mixture was heated at 70° C. for 1 h with stirring. Aftercooling to 23° C., the product solution was concentrated under reducedpressure to afford the title compound as a colorless solid (3.28 g,˜100%). TLC (ethyl acetate): R_(f)=0.37 (p-anisaldehyde). ¹H NMR (500MHz, CD₃OD) δ 4.67 (dd, J=12.7, 2.9 Hz, 1H), 4.57 (dd, J=12.7, 9.8 Hz,1H), 4.44-4.39 (m, 1H), 3.70-3.58 (m, 2H), 2.62-2.58 (m, 2H), 2.02-1.97(m, 1H). ¹³C NMR (126 MHz, CD₃OD) δ 80.0, 73.3, 70.3, 63.5. FTIR (neat),cm⁻¹: 3389 (br), 2930 (m), 2496 (m), 1547 (s), 1424 (s), 1385 (s), 1219(s), 1078 (s), 1038 (s). HRMS (ESI): Calcd for (C₄H₉NO₅+Na)⁺: 174.0373,Found: 174.0362.

3-Nitro-3-deoxy-α-v-galactose (S7)

A 50-mL round-bottom flask was charged with a magnetic stir bar,(2R,3R)-4-nitrobutane-1,2,3-triol S6 (775 mg, 5.13 mmol) and water (1.03mL). The solution was cooled to 0° C. Aqueous glyoxal solution (40 wt.%, 0.706 mL, 6.15 mmol, 1.20 equiv) and an aqueous solution of sodiumcarbonate (1.0 M, 0.513 mL, 0.513 mmol, 0.10 equiv) were addedsequentially via syringe. After 2 h at 0° C., sufficient 1 N HCl wasadded to the product solution to achieve pH 7. The solution was thenconcentrated under reduced pressure. The oil residue was diluted with5:1 ethyl acetate:methanol (10 mL), and the resulting solution wasfiltered through a thin pad of silica-gel (5 g). The filter cake wasrinsed with 5:1 ethyl acetate:methanol (40 mL). The filtrate wasconcentrated and the residue was diluted with 1:1 toluene:isopropanol(20 mL). After stirring for 16 h at 23° C., the solution wasconcentrated under a stream of nitrogen, and the solid residue wastriturated with 5:1 ethyl acetate:isopropanol (20 mL) with sonication.The resulting suspension was filtered through a sintered glass funnel(medium porosity), and the filter cake was rinsed with 5:1 ethylacetate:isopropanol (5 mL). Further drying of the collected solids atreduced pressure (0.2 mmHg) afforded the title compound as an off whitepowder (290 mg, 27%). TLC (100% ethyl acetate): R_(f)=0.21(p-anisaldehyde). Mp=132-134° C. ¹H NMR (α-anomer, 500 MHz, CD₃OD) δ5.22 (d, J=3.9 Hz, 1H), 4.79 (dd, J=10.7, 3.4 Hz, 1H), 4.48 (dd, J=10.7,3.9 Hz, 1H), 4.40 (dd, J=3.4, 1.5 Hz, 1H), 4.12 (app t, J=6.4 Hz, 1H),3.71 (dd, J=11.2, 6.4 Hz, 1H), 3.66 (dd, J=11.2, 6.4 Hz, 1H). ¹³C NMR(α-anomer, 126 MHz, CD₃OD) δ 93.7, 88.8, 71.0, 69.6, 65.9, 62.0. FTIR(neat), cm⁻¹: 3354 (br), 2942 (m), 2481 (m), 1715 (s), 1553 (s), 1375(s), 1148 (s), 1051 (s), 976 (s). HRMS (ESI): Calcd for (C₆H₁₁NO₇+Na)⁺:232.0428, Found: 232.0421.

(R)-4-((R)-1-(benzhydryloxy)-2-nitroethyl)-2,2-dimethyl-1,3-dioxolane(S8)

A 200-mL round-bottom flask was charged with a magnetic stir bar,(R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethan-1-ol S5 (934 mg,4.89 mmol, 1 equiv) and toluene (48.9 mL). (Diazomethylene)dibenzene(1.90 g, 9.77 mmol, 2.00 equiv) was added, affording a purple solution.The reaction mixture was heated at reflux with stirring. After 1 h, thepurple color had changed to yellow. The solution was cooled to 23° C.and then was concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel (30% ethylacetate-hexanes) to afford the title compound as a white solid (1.60 g,92%). TLC (20% ethyl acetate-hexanes): R_(f)=0.30 (UV, phosphomolybdicacid). ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.26 (m, 10H), 5.61 (s, 1H), 4.64(dd, J=12.7, 3.9 Hz, 1H), 4.57 (dd, J=12.7, 8.3 Hz, 1H), 4.53-4.47 (m,1H), 4.23-4.19 (m, 1H), 4.00-3.94 (m, 2H), 1.45 (s, 3H), 1.31 (s, 3H).¹³C NMR (126 MHz, CDCl₃) δ 141.3, 141.0, 128.6, 128.4, 128.1, 127.8,127.3, 126.9, 109.9, 83.7, 75.8, 74.4, 74.1, 64.7, 26.0, 24.3. FTIR(neat), cm⁻¹: 3063 (m), 3030 (m), 2988 (m), 2936 (m), 2895 (m), 1555(s), 1495 (s), 1454 (s), 1261 (s), 1213 (s), 1155 (s), 1059 (s), 920(s), 742 (s), 696 (s). HRMS (ESI): Calcd for (C₂₀H₂₃NO₅+Na)⁺: 380.1468,Found: 380.0451.

(2R,3R)-3-(benzhydryloxy)-4-nitrobutane-1,2-diol (S9)

A 200-mL round-bottom flask was charged with a magnetic stir bar,(R)-4-((R)-1-(benzhydryloxy)-2-nitroethyl)-2,2-dimethyl-1,3-dioxolane S8(1.60 g, 4.48 mmol, 1 equiv), acetic acid (11.19 ml) and water (3.73ml). The resulting solution was heated at 70° C. for 1 h with stirring.After cooling to 23° C., the reaction mixture was concentrated underreduced pressure to afford the title compound as a colorless oil (1.40g, 99%). TLC (50% ethyl acetate-hexanes): R_(f)=0.21 (UV,phosphomolybdic acid). ¹H NMR (500 MHz, CDCl₃) δ 7.41-7.27 (m, 10H),5.57 (s, 1H), 4.71 (dd, J=12.7, 4.4 Hz, 1H), 4.63 (dd, J=12.7, 6.8 Hz,1H), 4.39 (dt, J=6.8, 4.4 Hz, 1H), 3.81-3.75 (m, 1H), 3.68-3.63 (m, 1H),2.62-2.58 (m, 2H), 2.02-1.97 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 140.8,140.7, 128.8, 128.5, 128.3, 127.9, 127.4, 126.8, 83.7, 76.0, 75.1, 71.1,62.6. FTIR (neat), cm⁻¹: 3553 (br), 3422 (br), 3063 (m), 3030 (m), 2928(m), 2889 (m), 1553 (s), 1495 (s), 1454 (s), 1424 (s), 1381 (s), 1076(s), 918 (s), 743 (s), 698 (s). HRMS (ESI): Calcd for (C₁₇H₁₉NO₅+Na)⁺:340.1155, Found: 340.1167.

3-Nitro-3-deoxy-4-O-benzhydryl-v-galactose (S10)

A 50-mL round-bottom flask was charged with a magnetic stir bar,(2R,3R)-3-(benzhydryloxy)-4-nitrobutane-1,2-diol S9 (1.00 g, 3.15 mmol,1 equiv), dichloromethane (1.38 mL) and water (0.63 mL). The solutionwas cooled to 0° C. Aqueous glyoxal solution (40 wt. %, 0.434 mL, 3.78mmol, 1.20 equiv) and an aqueous solution of sodium carbonate (1.0 M,0.315 mL, 0.315 mmol, 0.10 equiv) were added sequentially via syringe.The resulting biphasic mixture was stirred vigorously at 4° C. After 18h, brine (20 mL) was added and the mixture was extracted with ethylacetate (3×20 mL). The combined organic layers were dried over magnesiumsulfate, and the dried solution was concentrated. The residue waspurified by column chromatography over silica gel (70% ethylacetate-hexanes) to afford the title compound as a white amorphous solid(2:1 anomeric mixture, 684 mg, 58%). TLC (100% ethyl acetate):R_(f)=0.21 (p-anisaldehyde). ¹H NMR (2:1 α:β anomeric mixture, 500 MHz,CD₃OD) α-anomer: δ 7.36-7.22 (m, 10H), 5.49 (s, 1H), 5.28 (d, J=3.9 Hz,1H), 4.74 (dd, J=10.7, 2.9 Hz, 1H), 4.64 (dd, J=10.7, 3.9 Hz, 1H), 4.48(dd, J=2.9 Hz, 1H), 4.12 (d, J=6.8 Hz, 1H), 3.59 (dd, J=11.2, 6.8 Hz,1H), 3.35-3.30 (m, 1H). β-anomer: δ 7.36-7.22 (m, 10H), 5.48 (s, 1H),4.58 (dd, J=10.7, 3.4 Hz, 1H), 4.54 (d, J=7.8 Hz, 1H), 4.44 (dd, J=3.4Hz, 1H), 4.35 (dd, J=10.7, 7.8 Hz, 1H), 3.68-3.62 (m, 2H), 3.35-3.30 (m,1H). ¹³C NMR (2:1 α:β anomeric mixture, peaks are reported collectively,126 MHz, CD₃OD) δ 143.3, 142.5, 129.2, 128.8, 128.7, 128.6, 128.3,128.2, 93.6, 90.1, 87.4, 85.0, 84.9, 77.7, 74.6, 74.2, 71.7, 69.5, 66.4,61.9. FTIR (neat), cm¹: 3402 (br), 3065 (m), 3030 (m), 2982 (m), 2942(m), 1736 (s), 1709 (s), 1495 (s), 1454 (s), 1373 (s), 1244 (s), 1142(s), 1076 (s), 1042 (s), 1009 (s), 743 (s), 698 (s). HRMS (ESI): Calcdfor (C₁₉H₂₁NO₇+Na)⁺: 398.1210, Found: 398.1227.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (J):

or salt thereof, wherein: R^(1a) is —N(R^(S))₂, —NR^(S)(OR^(S)), or offormula:

each of R^(2a) and R^(3a) is independently hydrogen, halogen, optionallysubstituted C₁-C₆ alkyl, or —OR^(SO); X^(S) is a bond, —C(═O)—,—C(═NR^(SN))—, —S(═O)—, or —S(═O)₂—; L^(S2) is a bond, —NR^(S)—, —O—, or—S—, or a linking group selected from the group consisting of optionallysubstituted alkylene, optionally substituted alkenylene, optionallysubstituted alkynylene, optionally substituted heteroalkylene,optionally substituted heteroalkenylene, and optionally substitutedheteroalkynylene, and combinations thereof; each R^(S) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, an oxygen protecting group whenattached to an oxygen atom, a nitrogen protecting group when attached toa nitrogen atom, or a sulfur protecting group when attached to a sulfuratom, or two R^(S) attached to the same nitrogen atom are taken togetherto form ═N₂ or an optionally substituted heterocyclyl or heteroarylring; each of R^(7a) and R^(8a) is independently optionally substitutedC₁-C₆ alkyl, optionally substituted carbocyclyl, optionally substitutedaryl, optionally substituted heterocyclyl, optionally substitutedheteroaryl, optionally substituted acyl, or a nitrogen protecting group,or R^(7a) and R^(8a) are joined to form an optionally substitutedheterocyclyl or heteroaryl ring; each R^(SN) is independently hydrogen,optionally substituted C₁-C₆ alkyl, or a nitrogen protecting group, ortwo R^(SN) attached to the same nitrogen atom are joined to form anoptionally substituted heterocyclyl or heteroaryl ring; each of R^(4a)and R^(4b) is independently hydrogen, halogen, optionally substitutedC₁-C₆ alkyl, or —OR^(SO); and each of R⁵, R⁶ and R^(SO) is independentlyhydrogen, optionally substituted C₁-C₆ alkyl, a carbohydrate, or anoxygen protecting group; provided R^(1a) is not:


2. The compound of claim 1, wherein the compound is of Formula (J-1),(J-d-1), (J-m-1), or (J-m-1-A):

or salt thereof.
 3. The compound of claim 1, or salt thereof, whereinR^(7a) and R^(8a) are methyl.
 4. The compound of claim 1, or saltthereof, wherein R^(2a) is hydrogen or methyl.
 5. The compound of claim1, or salt thereof, wherein R^(1a) is —N(R^(S))₂.
 6. The compound ofclaim 5, or salt thereof, wherein R^(1a) is:


7. The compound of claim 1, or salt thereof, wherein R^(1a) is—NHC(═O)R^(S), —NHC(═O)OR^(S), or —NHC(═O)N(R^(S))₂.
 8. The compound ofclaim 7, or salt thereof, wherein R^(1a) is:


9. The compound of claim 1, or salt thereof, wherein R^(1a) is—NHC(═NR^(SN))R^(S), —NHC(═NR^(SN))OR^(S), —NHC(═NR^(SN))N(R^(S))₂, or—NHS(═O)₂R^(S).
 10. The compound of claim 9, or salt thereof, whereinR^(1a) is:


11. A compound of Formula (K):

or salt thereof, wherein: R^(1b) is —N(R^(S))₂, —NR^(S)(OR^(S)), or offormula:

each of R^(2b) and R^(3b) is independently hydrogen, halogen, optionallysubstituted C₁-C₆ alkyl, or —OR^(SO); X^(S) is a bond, —C(═O)—,—C(═NR^(SN))—, —S(═O)—, or —S(═O)₂—; L^(S2) is a bond, —NR^(S)—, —O—, or—S—, or a linking group selected from the group consisting of optionallysubstituted alkylene, optionally substituted alkenylene, optionallysubstituted alkynylene, optionally substituted heteroalkylene,optionally substituted heteroalkenylene, and optionally substitutedheteroalkynylene, and combinations thereof; each R^(S) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, an oxygen protecting group whenattached to an oxygen atom, a nitrogen protecting group when attached toa nitrogen atom, or a sulfur protecting group when attached to a sulfuratom, or two R^(S) attached to the same nitrogen atom are taken togetherto form ═N₂ or an optionally substituted heterocyclyl or heteroarylring; R^(SN) is hydrogen, optionally substituted alkyl, or a nitrogenprotecting group; each of R^(4a) and R^(4b) is independently hydrogen,optionally substituted C₁-C₆ alkyl, or —OR^(SO); and each of R⁵, R⁶ andR^(SO) is independently hydrogen, halogen, optionally substituted C₁-C₆alkyl, a carbohydrate, or an oxygen protecting group; provided R^(1b) isnot:


12. The compound of claim 11, wherein the compound is of Formula (K-1),(K-d-1), (K-m-1), (K-m-1-A):

or salt thereof.
 13. The compound of claim 11, or salt thereof, whereinR^(2b) is hydrogen or methyl.
 14. The compound of claim 11, or saltthereof, wherein R^(1b) is —N(R^(S))₂.
 15. The compound of claim 14, orsalt thereof, wherein R^(1b) is:


16. The compound of claim 11, or salt thereof, wherein R^(1b) is—NHC(═O)R^(S), —NHC(═O)OR^(S), or —NHC(═O)N(R^(S))₂.
 17. The compound ofclaim 16, or salt thereof, wherein R^(1b) is:


18. The compound of claim 11, or salt thereof, wherein R^(1b) is—NHC(═NR^(SN))R^(S), —NHC(═NR^(SN))OR^(S), or —NHC(═NR^(SN))N(R^(S))₂.19. The compound of claim 11, or salt thereof, wherein R^(1b) is—NHS(═O)₂R^(S).
 20. The compound of claim 11, or salt thereof, whereinR^(1b) is: